ES2350013T3 - DERIVATIVES OF TIAZOLO-PYRIMIDINE / PIRIDINA-UREA AS AN ADENOSINE RECEIVER ANTAGONISTS A2B. - Google Patents

Abstract

A compound of the formula I ** Formula ** R1 5 in which X is C or N, R1 is C1-4 alkoxy, R2 is hydrogen, hydroxy, C1-2 alkoxy or C1-2 alkylthio, R3 is hydrogen or alkyl C1-3, R4 is C1-4 alkyl substituted by aryl, aroyl, aryloxy, arylsulfonyl, aralkylamino, or aroylamino, or R3 and R4 together with the urea nitrogen to which they are attached form a heterocyclic ring of 5 or 6 links of the formula ** Formula ** in which R3 and R4 are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, It is already a saturated or partially unsaturated alkyl segment of 2 to 3 carbons of the ring which It has an aromatic substituent selected from the group consisting of aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, NHONSXRN 2 NR3R4 IN R4 R3 Already aryloxyalkyl, aryloxyalkylamino and aroylamino, and may also have 0, 1 or 2 non-aromatic substituents chosen from hydroxy, amino, lower alkylamino, lower alkanoylamino, oxo, cyan or, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) carbamoyl, or R3 and R4 together with the urea nitrogen to which they are attached form a 5 or 6 link heterocyclic ring of the formula Yh R3 N R4 in which R3 and R4 they are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, Yh is a saturated heteroalkyl segment of 2 or 3 ring atoms, one of which is a heteroatom and Yh is substituted by an aromatic group , which in the case of a carbon atom of the ring is chosen from the group consisting of aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino or, in the case of nitrogen, is chosen from the group formed by aryl, aralkyl, aroyl, arylhydroxymethylalkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, arylsulfonyl, aryloxyalkyl, arylaminoalkyl and aroylaminoalkyl, or R3 and R4 together with the urea nitrogen to which they are attached dinyl, which is benzo-fused with an unsubstituted or mono-, di- or trisubstituted phenyl, or R3 and R4 together with the urea nitrogen to which they are attached form a piperidinyl, which is spiro-fused with a saturated heterocyclic ring of 5 or 6 links containing 1 or 2 heteroatoms, said heterocyclic ring is attached or benzo-fused with an unsubstituted or mono-, di- or tri-substituted phenyl and said heterocyclic ring may also have 0, 1 or 2 non-aromatic substituents chosen from lower alkyl, acyl and lower alkylsulfonyl, or R3 and R4 together with the urea nitrogen to which they are attached form a 2,5-diaza- [2.2.1] -bicycloheptane substituted in position 5 or 2,5-diaza - [3.3.0] -bicyclooctane substituted at position 5, said substituent at position 5 is selected from the group consisting of aryl, aralkyl, aroyl, arylsulfonyl, aryloxyalkyl and arylhydroxymethylalkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, or pharmaceutically acceptable salts or esters bles thereof, wherein the term "lower alkyl", alone or in combination, means an alkyl group containing a maximum of six carbon atoms.

Description

The present invention relates to compounds of the formula I:

R1

and pharmaceutically acceptable salts and esters of the

10 themselves, in which R1, R2, R3 and R4 have the meanings defined below. It is believed that these compounds act primarily as A2B adenosine receptor antagonists and therefore that have potential for the treatment of diabetes,

15 diabetic retinopathy, asthma and diarrhea. The present invention refers to compounds of the formula I and their salts and esters pharmaceutically acceptable, to obtain and manufacture medicines that contain them for use in the control or prevention of diseases just mentioned

20 swims, especially diabetes. Adenosine is an autocoid produced in many tissues, which mediates several functions through four sub- types of receiver, that of the A1, A2A, A2B and A3. The four of them receptors belong to the group of receptors united over

25 G protein (GPCR), which contain seven hydrophobic domains

helical, which extend into the plasma membrane and are connected by extracellular hydrophilic loops and intracellular The A1 and A3 receptors join the Gi and Go proteins, while the A2A receptors and A2B bind to Gs proteins. Because of these differences, the adenosine signals an increase in intracellular levels of cAMP through its action through A2A receptors and A2B and a decrease through the A1 and A3 receptors. In addition, adenosine increases intracellular levels of calcium ion through the A2B receptor, thanks to its fixation on Gq proteins.

The compounds of the formula I have a potent antagonistic activity of the human adenosine receptor A2B, which can be measured in a CHO-A2B-cAMP assay.

The study of the role of the functional activity of the A2B receptor in several cell types has been complicated by the absence of selective A2B agonists and it antagonists against the three remaining receptors. By example, the functional activity of A2B receptor is deduced due to the absence of effects of agonists and antagonists selective in the remaining three adenosine receptors, while issuing responses with the NECA, a potent and non-selective adenosine receptor agonist. Usually, the role of the A2B receptor in a given type of cells is identifies when the following singular order of agonist power; NECA (non-selective)> PIA (selective agonist of A1)> IB-MECA (selective agonist of A3)> CGS-21680 (selective A2A agonist).

It has been determined that the relative agonist potency of adenosine against its four receptors and has been found to be A1 (EC50 - 0.31 µM)> A3 (EC50 - 0.29 µM)> A2A (EC50 - 0.7 µM)> A2B (EC50 - 24 µM), which suggests a sun A2B receptor exclusive under stress conditions Chronic, very oxidizing, which include, but are not limited to: hyperglycemia, mast cell activation and inflammation of the gastrointestinal tract. Despite the low agonist power of adenosine with the A2B receptor have been described numerous compounds that have high antagonistic potency of the A2B receiver.

Using specific agonists and antagonists, the Eisai researchers have revealed the key role of A2B receptor antagonism to inhibit hepatic glucose production and it has also been shown that a potent inhibitor of the A2B receptor antagonist and a hepatocyte glucose production inhibitor rat rats reduce fasting glucose levels and in a state fed by KK-Ay mice, a good model recognized type 2 diabetes. Therefore, the compounds of the present invention have utility to prevent and / or treat type 2 diabetes

A2B receptors are also present in the plasma membranes of endothelial cells and it has Observed that they stimulate their growth. Therefore, this will lead to the growth of new blood vessels (angiogenesis). An object of this invention is to prevent and / or treat

diseases characterized by abnormal growth of blood vessels, as in diabetic retinopathy. Applying immunofluorescence techniques with an A2B specific anti-human antibody, the presence is verified.

5 of A2B receptors in human lung mast cells obtained of asthmatic patients cells by bronchoalveolar lavage. Therefore, the compound of the formula I allows to apply a method of prevention and / or treatment of asthma, bronchospastic and allergic diseases as well as diseases

10 obstructive airways.

A2B receptors have been found in the colon, in basolateral domains of intestinal epithelial cells and increase chloride ion secretion in response to inflammation of the gastrointestinal tract in diseases

15 of the diarrhea type. Therefore, the compounds of the formula I allow to apply a method of treatment of disorders inflammatory of the gastrointestinal tract, including diarrhea.

In more detail, the present invention relates to 20 a compound of the formula I

R1

in which X is C or N, R1 is C1-4 alkoxy,

image 1

image2

R2 is hydrogen, hydroxy, C1-2 alkoxy or C1-2 alkylthio, R3 is hydrogen or C1-3 alkyl, R4 is C1-4 alkyl substituted by aryl, aroyl, aryloxy, arylsulfonyl, aralkylamino, or aroylamino,

5th R3 and R4 together with the urea nitrogen to which they are attached form a heterocyclic ring of 5 or 6 links of the formula

10 link R3 and R4 are both CH2ounoes CH2yelotroesun methylene monosubstituted by a lower alkyl, It is already a saturated or partially unsaturated alkyl segment 2 to 3 carbons of the ring having an aromatic substituent selected from the group consisting of aryl, aralkyl,

Aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino, e You can now also have 0, 1 or 2 non-aromatic substituents chosen between hydroxy, amino, lower alkylamino, alkanoylamino lower, oxo, cyano, carboxy, hydroxyalkylamino, carbamoyl

20 and (lower alkyl) carbamoyl, or R3 and R4 together with the urea nitrogen to which they are attached they form a heterocyclic ring of 5 or 6 links of the formula

image3

in which R3 and R4 are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, Yh is a saturated heteroalkyl segment of 2 or 3 atoms of the

5 ring, one of which is a heteroatom and Yh is substituted by an aromatic group, which in the case of an atom of Ring carbon is chosen from the group formed by aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino or, in the case

10 of nitrogen, is chosen from the group formed by aryl, aralkyl, aroyl, arylhydroxymethyl alkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, arylsulfonyl, aryloxyalkyl, arylaminoalkyl and aroylaminoalkyl, or

15 R3 and R4 together with the urea nitrogen to which they are attached they form a piperidinyl or pyrrolidinyl, which is benzofused with an unsubstituted or mono-, di- or trisubstituted phenyl, or

20 R3 and R4 together with the urea nitrogen to which they are attached they form a piperidinyl, which is spiro-fused with a 5 or 6-link saturated heterocyclic ring containing 1 or 2 heteroatoms, said heterocyclic ring is attached or benzo-fused with an unsubstituted or mono-, di-o phenyl

Tri-substituted and said heterocyclic ring may have also 0, 1 or 2 non-aromatic substituents chosen from lower alkyl, acyl and lower alkylsulfonyl,

or R3 and R4 together with the urea nitrogen to which they are attached they form a 2,5-diaza- [2.2.1] -bicycloheptane substituted in position 5 or a 2,5-diaza- [3.3.0] -bicyclooctane substituted in

5 position 5, said substituent of position 5 is chosen between the group consisting of aryl, aralkyl, aroyl, arylsulfonyl, aryloxyalkyl and arylhydroxymethyl alkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl,

or pharmaceutically acceptable salts or esters thereof.

10 Preferred compounds among those just described are those, in which R2 is hydrogen or hydroxy, R3 is hydrogen or C1-3 alkyl and R4 is C1-4 alkyl substituted by aryl, aralkyl, aroyl,

Aryloxy, arylsulfonyl, aralkylamino or aroylamino.

Other preferred compounds among those described above are those, in which R3 and R4 together with the urea nitrogen to which they are attached they form a heterocyclic ring of 5 or 6 links of the

20 formula

in which R3 and R4 are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, It is already a saturated or partially unsaturated alkyl segment

25 of 2 to 3 carbons of the ring having an aromatic substituent selected from the group consisting of aryl, aralkyl,

image2

image3

aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino, e You can now also have 0, 1 or 2 non-aromatic substituents chosen between hydroxy, amino, lower alkylamino, alkanoylamino

5 lower, oxo, cyano, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) carbamoyl, or R3 and R4 together with the urea nitrogen to which they are attached they form a heterocyclic ring of 5 or 6 links of the

10 formula

in which R3 and R4 are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, Yh is a saturated heteroalkyl segment of 2 or 3 atoms of the

15 ring one of which is a heteroatom and Yh is substituted by an aromatic group, which in the case of an atom of Ring carbon is chosen from the group formed by aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino or, in the case

20 nitrogen, is chosen from the group formed by aryl, aralkyl, aroyl, arylhydroxymethyl alkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, arylsulfonyl, aryloxyalkyl, arylaminoalkyl and aroylaminoalkyl. In such compounds, R1 is preferably methoxy and R2 is hydrogen or

25 hydroxy.

Other preferred compounds of formula I are those, in which R3 and R4 together with the urea nitrogen to which they are attached they form a piperidinyl or pyrrolidinyl ring, which is

5 benzo-fused with an unsubstituted or mono-, di-o phenyl tri-substituted In such compounds, R1 is preferably Methoxy and R2 is hydrogen or hydroxy.

Other preferred compounds of formula I are those, in which

10 R3 and R4 together with the urea nitrogen to which they are attached they form a piperidinyl or pyrrolidinyl, which is spiro-fused with a saturated 5 or 6-link heterocyclic ring containing 1 or 2 heteroatoms, said heterocyclic ring is attached or benzo-fused with an unsubstituted phenyl

Tuir or mono-, di- or tri-substituted and said heterocyclic ring may also have 0, 1 or 2 non-aromatic substituents chosen from lower alkyl, acyl and alkylsulfonyl lower. In such compounds, R1 is preferably methoxy and R2 is hydrogen or hydroxy.

Other preferred compounds among those defined above are those, in which the heterocyclic ring formed with R3 and R4 is pyrrolidinyl, piperidinyl or piperazinyl. Other preferred compounds among those defined before

25 riormente are those that have the formula:

image4

R1

in which R5 is aryl, aralkyl, aroyl, aryloxyalkyl, arylsulfonyl, arylaminoalkyl, arylhydroxymethyl alkyl, arylalkoxy

Methylalkyl, arylcarboxymethyl alkyl or aroylaminoalkyl. In such compounds, R1 is preferably methoxy and R2 is hydrogen or hydroxy.

Other preferred compounds among those described above they are the ones with the formula

image5 R1 N image5

X H

image5 R6

N image5

image5 R7

SN image5

R2

N

R8

OR

10, wherein one of R6-R8 is CH2, one of R6-R8 is CH2 or CH (OH) and one of R6-R8 is a methylene having an aromatic substituent or two substituents: one aromatic and one non-aromatic, said aromatic substituent is chosen from aryl, aralkyl, Aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino and said non-aromatic substituent is selected from hydroxy, cyano, amino, lower alkylamino, lower alkanoylamino, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) carba20 moílo. In such compounds, R1 is preferably methoxy and R2 It is hydrogen or hydroxy. More preferably, the substitute

The aromatic agent is in turn substituted by one or two substituents chosen independently from the group formed by halogen, hydroxy, lower alkoxy, haloalkyl and haloalkoxy. Preferably, one or two substituents are chosen

5 independently among the group formed by chlorine, fluorine, methoxy, perfluoralkyl and perfluoromethoxy. Other preferred compounds among those defined previously they are those that have the formula

image5 R1 N image5

X H

image5 R9N image5

SN image5 R2 N

R10

OR

10 in which one of R9 and R10 is CH2 and the other is a methylene that It has an aromatic substituent or two substituents: one aromatic and other non-aromatic, said aromatic substituent is chosen from aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxial

15-caylamino and aroylamino and said non-aromatic substituent is Choose between hydroxy, cyano, amino, alkylamino, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) carbamoyl. In such compounds, R1 is preferably methoxy and R2 It is hydrogen or hydroxy. Preferably, the aromatic ring

20 of the aryl moiety is in turn substituted by one or two substituents chosen from the group consisting of halogen, hydroxy, lower alkoxy, haloalkyl and haloalkoxy. With Preferably, one or two substituents are independently selected from the group consisting of chlorine, fluorine, methoxy,

Perfluoralkyl and perfluoromethoxy.

Other preferred compounds are those that have the formula

R1

in which

R11 is aryl, aroyl, aryloxy or arylsulfonyl and n is 1-4. With Preferably, R1 is methoxy and R2 is hydrogen or hydroxy. With Preferably, the aromatic ring of the aryl moiety R11 is substituted in turn by one or two substituents chosen among the group consisting of halogen, hydroxy, infe alkoxy

10 rior, haloalkyl and haloalkoxy. Preferably, one or two substituents are chosen independently from the group formed by chlorine, fluorine, methoxy, perfluoralkyl and perfluoromethoxy Other preferred compounds among those described above

15 are those of the formula

image6

image5 R1

R12

N image5 XH

N image7 N

image5 SNR2

N

O o

in which

Z is carbon or nitrogen and

R12 is unsubstituted or mono-, di- or tri-substituted phenyl. Preferably, R1 is methoxy and R2 is hydrogen or hydroxy.

image8

Other preferred compounds among those described above they are the ones with the formula

R1

wherein R13 is hydrogen, lower alkyl or lower alkyl nyl alkyl5 and R14 is hydrogen, halogen, lower alkyl

or lower alkylsulfonyl. Preferably, R1 is methoxy and R2 is hydrogen or hydroxy.

Other preferred compounds among those described above they are the ones with the formula

image5 R1

image5 R15

N image5

H

X

image5 N

N image5

N

R2

S

N

OR

10 in which R15 is chosen from the group consisting of aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino, aroylamino, arylhydroxymethylalkyl, arylcarboxymethyl alkyl and arylalkoxymethyl alkyl. Preferably, R1 is methoxy and R2 is hydrogen or hydroxy Other preferred compounds among those described above are those of the formula

image9

in which R16 is chosen from the group consisting of aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino, aroylamino, arylhydroxy

5-methylalkyl, arylcarboxymethyl-alkyl and arylalkoxymethyl-alkyl. Preferably, R1 is methoxy and R2 is hydrogen or hydroxy

Preferred compounds among those described above are those chosen from the group consisting of:

4- (3-Trifluoromethyl-benzyl) -piperazine-1-carboxylic acid 10 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

15-chloro-benzyl) -piperazine-1-carboxylic acid, 4- (3-Benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide,

4- (3-Methoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (3,4-Difluoro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

Chloro-4-methoxy-benzyl) -piperazine-1-carboxylic acid,

(7-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4- (3-nitrobenzyl) -piperazine-1-carboxylic acid and Methyl 3- [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-ylmethyl] -benzoate.

Other preferred compounds among those described above are those chosen from the group formed by: 4 (3,5-Dimethoxy-benzyl) piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3difluoromethoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (3,5-Dichloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- [3 (2-Hydroxy-ethoxy) -benzyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- [1 (3-Chloro-phenyl) -ethyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Phenethyl-piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-3-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide and 4- (6-Trifluoromethyl-pyridin-3-ylmethyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 4- (5-Chloro-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, {3- [4- (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) piperazin-1-ylmethyl] -phenoxy} -acetic acid, 4 (3,5-Dichloro-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (5-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3fluor-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (5fluor-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2-Hydroxy-3-methyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 2-hydroxy-3- [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-ylmethyl] -benzoic acid, 4- (6morpholin-4-yl-pyridin-3-yl-methyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Pyridine-2-ylmethyl-piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide and 4-Benzyl-piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 4- (4-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

chloro-2-methanesulfonyl-benzyl) -piperazine-1-carboxylic acid,

4 (3,4-Dichloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Methoxy-3-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3ciano-4-methoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (3,5-bis-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- [2 (3-Trifluoromethyl-phenoxy) -ethyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-3-trifluoromethyl-benzoyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (6-Trifluoromethyl-pyridine-3-carbonyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-benzoyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-benzenesulfonyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide and 4- [3 (Trifluoromethyl) phenyl] piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 2- (4-Trifluoromethyl-phenyl) -morpholine-4-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 1 - [(7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide] 3-thiazol-2

piperidine-1,3-dicarboxylic acid ilamide,

4- (5methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide , 1- (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -3- (4-trifluoromethoxy-benzyl) -piperidine-3-carboxylate ethyl, 4'hydroxy-3 ', 4', 5 ', 6'-tetrahydro-2H- [2,4'] bipyridinyl (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide -1'-carboxylic, 3,4-Hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide Y 4 (1,3-Dihydro-isoindol-2-yl) -piperidine-1-carboxylic acid, trifluoroacetate (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 4- (4fluor-phenyl) -1-oxo-2,8-diazapiro [4,5] decane-8-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide , 5-Chloro-1,2-dihydro-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) 1- (methylsulfonyl) spiro [3H-indole-3,4'-piperidine] -1 ' -carboxamide, 1,2-dihydro-5-methoxy-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) 1-methylpyrro [3H-indole-3,4'-piperidine] -1'-carboxamide, 1- (cyclopropylmethyl) -1,2-dihydro-N- (7-methoxythiazol [5,4-d] pi

rimidin-2-yl) spiro [3H-indole-3,4’-piperidine] -1’-carboxamide,

1- (cyclopropylmethyl) -1,2-dihydro-5-chloro-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) spiro [3H-indole-3,4'-piperidine] -1 'carboxamide, 4- (4fluor-phenyl) -1-oxo-2,8-diaza-spiro [4.5] decane-8-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide Y 4oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 4- (3-phenyl-pyrrolidin-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2-Phenyl-pyrrolidin-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (2,3-dihydro-indol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (5-Chloro-2,3-dihydro-indole-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3- (3-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

trifluoromethyl-benzyl) -piperidine-1-carboxylic acid,

3-Benzyl-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide and 4- (2oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 4- (3-Trifluoromethyl-benzenesulfonyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Chloro-benzenesulfonyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (Toluene-4-sulfonyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-phenoxy) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-benzyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, Methyl 2- [1- (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperidine-4-sulfonyl] -benzoate 4- (3-Trifluoromethyl-benzyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 4- (3-Chloro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Hydroxy-4- (3-methoxy-phenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide,

4'hydroxy-6-trifluoromethyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [(7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide [[ 2,4 '] bipyridinyl-1'-carboxylic acid, 4-Acetylamino-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-amino-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-3-trifluoromethyl-benzylamino) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 [(6-Trifluoromethyl-pyridin-3-ylmethyl) -amino] -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide and 4- (4-Fluoro-3-trifluoromethyl-benzoylamino) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 3- (4-Chloro-benzyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3- (4-Trifluoromethyl-benzyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3 (Toluene-4-sulfonyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3- [2 (3-Trifluoromethyl-phenoxy) -ethylamino] -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide,

(R) 3- (4-Fluoro-3-trifluoromethyl-benzylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, (R) 3- (4-Fluoro-3-trifluoromethyl-benzoylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide and (S) 3- (4-Fluoro-3-trifluoromethyl-benzoylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 8-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide and 6-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide.

Other preferred compounds among those described above are those chosen from the group formed by: 4-fluor-N- {2- [3- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -ureido] -ethyl} -3-trifluoromethyl-benzamide, 1- [2- (4-fluor-3-trifluoromethyl-benzylamino) -ethyl] -3- (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -urea, 3- (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -1-methyl-1- [(7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 2- (3-Trifluoromethyl-phenoxy) -ethyl] urea-4- [1- (3-chloro-phenyl) -2-hydroxyethyl] -piperazine-1-carboxylic acid,

(3-Chloro-phenyl) - [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-yl] -methyl acetate, 4- [2methoxy-1- (3-trifluoromethyl-phenyl) -ethyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

5 liquor, 4-Hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide and (5-Hydroxy-7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

4-Hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid. Other preferred compounds among those described above are those chosen from the group formed by:

4-Hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-b] pyridine-2-yl) -amide, 3- (4-Fluoro-3-trifluoromethyl-benzylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-b] pyridin-2-yl) -amide Y

4- (3-Trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-b] pyridin-2-yl) -amide. The present invention further relates to compounds of the formula

R1

image 1

25 link

image2

X is C or N, R1 is C1-4 alkoxy, R2 is hydrogen, hydroxy, C1-2 alkoxy or C1-2 alkylthio, R3 is hydrogen or C1-3 alkyl,

R 4 is C 1-4 alkyl substituted by aryl, aroyl, aryloxy, arylsulfonyl, aralkylamino or aroylamino, or R3 and R4 together with the urea nitrogen to which they are attached they form a heterocyclic ring of 5 or 6 links of the

10 formula

in which R3 and R4 are both CH2 or one is CH2 and the other is mono-substituted by lower alkyl, It is already a saturated or partially unsaturated alkyl segment

15 from 2 to 3 carbons of the ring having an aromatic substituent selected from the group consisting of aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino, and may already have in addition 0, 1 or 2 non-aromatic substituents chosen from

20 hydroxy, amino, lower alkylamino, lower alkanoylamino, cyano, carboxy, hydroxyalkylamino, carbamoyl and (alkyl lower) carbamoyl, or R3 and R4 together with the urea nitrogen to which they are attached

25 form a 5 or 6 link heterocyclic ring of the formula

image3

in which R3 and R4 are both CH2 or one is CH2 and the other is mono-substituted by lower alkyl, Yh is a saturated heteroalkyl segment of 2 or 3 atoms of the

5 ring one of which is a heteroatom and Yh is substituted by an aromatic group, which in the case of an atom of Ring carbon is chosen from the group formed by aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino or,

10 in the case of nitrogen, the group consisting of aryl, aralkyl, aroyl, arylhydroxymethyl alkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, arylsulfonyl and aryloxyalkyl, or

15 R3 and R4 together with the urea nitrogen to which they are attached they form piperidinyl or pyrrolidinyl, which is benzo-fused with an unsubstituted or mono-, di- or tri-substituted phenyl, or

20 R3 and R4 together with the urea nitrogen to which they are attached they form piperidinyl, which is spiro-fused with a saturated 5 or 6 link heterocyclic ring containing 1 or 2 heteroatoms, said heterocyclic ring is attached or benzo-fused with an unsubstituted or mono-, di-o phenyl

Tri-substituted and said heterocyclic ring may have also 0, 1 or 2 non-aromatic substituents chosen from lower alkyl, acyl and lower alkylsulfonyl;

image10

or R3 and R4 together with the urea nitrogen to which they are attached they form a 2,5-diaza- [2.2.1] -bicycloheptane substituted in position 5 or a 2,5-diaza- [3.3.0] -bicyclooctane substituted in

5 position 5, said substituent of position 5 is chosen between the group consisting of aryl, aralkyl, aroyl, arylsulfonyl, aryloxyalkyl and arylhydroxymethyl alkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl,

or pharmaceutically acceptable salts and esters of the

10 previous compounds. Preferred compounds of the formula I are:

R1

in which R5 is aryl, aralkyl, aroyl, aryloxyalkyl, arylsulfonyl, arylaminoalkyl or aroylaminoalkyl,

image5 R1 N image5

X H image5 R6

N image5

image5 R7 III

SN image5

R2 N R8

OR

fifteen , wherein one of R6-R8 is CH2, one of R6-R8 is CH2 or CH (OH) and one of R6-R8 is substituted by an aromatic substituent or It has two substituents, one aromatic and one non-aromatic, said aromatic substituent is chosen from aryl, aralkyl, Aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino and said their

image11

Non-aromatic substituent is chosen from hydroxy, cyano, amino, lower alkylamino, lower alkanoylamino, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) carbamoyl,

R1

5 in which one of R9 and R10 is CH2 and the other is substituted by an aromatic substituent or has two substituents, one aromatic and non-aromatic, said aromatic substituent is Choose between aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkyl

10 amino and aroylamino and said non-aromatic substituent is chosen between hydroxy, cyano, amino, alkylamino, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) carbamoyl and

image5 R1 N image5

X H

N image5

SN image5 image5 image12 2

image13 R11 V R2 NO

in which R11 is aryl, aroyl, aryloxy or arylsulfonyl and n is 1-4. Preferred compounds of the formula I having a Spiro-fused piperidinyl group are:

R1

R12

image5 NX

H

N image7 N VI

image5 SNR2

N O O

wherein Z is carbon or nitrogen and R12 is unsubstituted or mono-, di- or tri-substituted phenyl,

R1

5 wherein R13 is hydrogen, lower alkyl or lower alkylsulfonyl and R14 is hydrogen, halogen, lower alkyl or lower alkylsulfonyl,

R1

image5 R15

image5 N image5 HX VIII image5 NN image5

N

R2 SN O

in which R15 is chosen from the group consisting of aryl,

10 aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino, aroylamino and arylhydroxymethyl alkyl, arylcarboxymethyl alkyl and arylalkoxymethyl alkyl Y

image14

image15

in which R16 is chosen from the group consisting of aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino, aroylamino, arylhydroxy

5-methylalkyl, arylcarboxymethyl-alkyl and arylalkoxymethyl-alkyl.

For the compounds of the formulas I-IX it is preferred that R1 = methoxy or ethoxy, with particular preference being methoxy R2 is preferably hydrogen or hydroxy.

10 In this description "alkyl" means a hydrocarbon aliphatic linear chain, branched or totally or partially cyclic The term "lower alkyl", alone or in combination (for example, as part of "lower alkoxy", "alkanoyl

15 lower ”,“ lower alkylamino ”, etc. defined below), means an alkyl group that contains a maximum of six carbon atoms. "Haloalkyl" and "hydroxyalkyl" they mean a substituted lower alkyl moiety. The term "acyl" indicates -C (O) -alkyl lower.

20 The term "heteroatom" means N, O or S. The term "heterocycle" or "heterocyclic ring" means a monocyclic or bicyclic ring, saturated or partially unsaturated, consisting of carbon atoms and heteroatoms. Preferred heterocyclic rings are rings.

monocyclic 5 or 6 links or bicyclic rings 7 or 8 links that have 1-3 heteroatoms.

The term "aryl" means an aromatic ring 5 or 6 link monocyclic, substituted or unsubstituted, which can be totally carbocyclic or can contain one, two or three heteroatoms in the ring. The aryl can be replaced by one, two, three or four substituents. Every substituent is independently and preferably hydroxy, carboxy, nitro, nitrile, lower alkyl, lower alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, amino or lower alkylamino. Examples of aryl moieties include, but not limited to: optionally substituted phenyl, optionally substituted thiazolyl, optionally substituted pyrazinyl, optionally substituted pyrrolyl, pyrazinyl optionally substituted, optionally substituted pyridinyl, optionally substituted pyrimidinyl and the like.

The term "cycloalkyl" means an aliphatic ring 5 or 6 link monocyclic, substituted or unsubstituted, which can be totally carbocyclic or can contain one, two or three heteroatoms in the ring. The substituents of cycloalkyl are preferably lower alkyl, oxo or substituted or unsubstituted phenyl.

The term "aralkyl" means an alkyl moiety. lower or cycloalkyl, already defined previously, in which a hydrogen atom has been replaced by an aryl moiety already defined above, or additionally in the case of cycloalkyl, two adjacent carbon atoms have been benzo-fused with

a substituted or unsubstituted phenyl, to form a moiety bicyclic

The term "aryloxy" means an aryl group that is attached to the rest of the molecule by an oxygen atom. The preferred aryloxy group is phenoxy. "Aryloxyalkyl" means a lower alkyl substituent, in which it has replaced a hydrogen atom with an aryloxy group.

The term "aralkyloxy" means an aralkyl group. already defined, which is attached to the rest of the molecule through of an oxygen atom.

The term "arylhydroxymethyl alkyl" means a lower alkyl substituent, one of whose carbon atoms It has two substituents: an aryl group and a hydroxymethyl group.

The term "arylcarboxyalkyl" means a lower alkyl substituent, one of whose carbon atoms has two substituents: an aryl group and a carboxymethyl group.

The term "arylalkoxyalkyl" means a lower alkyl substituent, one of whose carbon atoms has two substituents: an aryl group and an alkoxymethyl group.

The term "aroyl" means an aryl group already defined above, attached to the rest of the molecule through a carbonyl group. Examples of aroyllo are benzoyl, 3-cyanobenzoyl and the like.

The term "arylsulfonyl" means an aryl moiety. attached to the rest of the molecule through the sulfur atom of

a sulfonyl group.

The term "aralkylamino" means an aralkyl group. attached to the rest of the molecule through the nitrogen atom of the amino group.

The term "aroylamino" means an attached aroyl group. to the rest of the molecule through the nitrogen atom of amino group.

The term "lower alkoxy" means an alkyl moiety. lower bound through an oxygen atom. Are examples of lower alkoxy groups without replacing methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, tert-butoxy and the like. "Haloalkoxy" is lower alkoxy substituted by halogen. He term "alkoxy" means an alkyl group attached through an oxygen atom

The term "carbamoyl" means the substituent carboxamide –C (O) -NH2. The term "(lower alkyl) carbamoyl" means that one or the hydrogen atoms of the Amide have been independently substituted by lower alkyl.

The term "lower alkanoyl" means lower alkyl groups attached to the rest of the molecule through a carbonyl group and encompasses within the meaning of the definition before groups of the formyl (methanoyl), acetyl type, propionyl and the like. "Lower alkanoylamino" means a lower alkanoyl group attached to the rest of the molecule a through an amino group. "Lower alkylamino" means a lower alkyl group attached to the rest of the molecule through of an amino group.

The term "halogen" means an atom chosen from chlorine, fluorine and bromine.

"IC50" indicates the concentration of a specific compound that is required to inhibit activity by 50% specific measure. The IC50 can be measured, among others, by The methods listed below.

"Pharmaceutically acceptable ester" means a compound of the formula I esterified by conventional methods having a carboxy group, said ester retains the Biological efficacy and properties of the compounds of the formula I and decompose "in vivo" (in the body) to generate the corresponding active carboxylic acid again. Therefore, at any time when the carboxy assumes that the compounds of the formula I they also cover pharmaceutically acceptable esters of the same.

More information regarding esters and the use of esters for the delivery of pharmaceutical compounds may be find in the Design of Prodrugs manual, coord. by Bundgaard, H. (Elsevier, 1985). See also, H. Ansel and col., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed., 1995) on pp. 108-109; Krogsgaard-Larsen, et al., Textbook of Drug Design and Development (2nd ed., 1996) in the pp. 152-191.

"Pharmaceutically acceptable salt" means the salts acid addition or conventional base addition salts, which retain the biological efficacy and properties of the compounds of the present invention and are

form by reaction with organic or inorganic acids not Toxic suitable or with suitable inorganic bases. The examples of acid addition salts include those derived from acids inorganic, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and acid derivatives organic, such as p-toluenesulfonic acid, acid salicylic acid, methanesulfonic acid, oxalic acid, acid succinic, citric acid, malic acid, lactic acid, acid fumaric and the like. Examples of addition salts of base include those derived from ammonium hydroxides, potassium, sodium and quaternary ammonium, for example the tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e. a drug) to obtain a salt thereof is a technique that pharmaceutical chemists know perfectly and apply when they claim improve physical and chemical stability, character hygroscopic, fluidity and solubility of compounds, see, e.g., H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed., 1995) on pp. 196 and 1456-1457.

The compounds of the formula (I) may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, by example racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers

or mixtures of diastereoisomer racemates. The forms optically active can be obtained by methods that are well

known in the art, for example by resolution of racemates, by asymmetric synthesis or by chromatography asymmetric (chromatography through a chiral adsorbent or with a chiral eluent). The invention contemplates all mentioned forms.

The compounds of the formula (I) can be obtained by the methods indicated below, by methods described in the examples or by similar methods. The subject matter experts already know the reaction conditions appropriate for each of the concrete steps. The starting materials are commercial or composite products which can be obtained by methods similar to those described to below or in the examples or by already known methods of The technique.

The compounds of the formula I and / or their pharmaceutically acceptable salts can be used as medicaments, eg in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can administer, by for example, orally, eg in the form of tablets, tablets coated, dragee, hard or soft gelatin capsules, solutions, emulsions or suspensions; rectally, e.g. in the form of suppositories; parenterally, e.g. in shape of injectable solutions or infusion solutions; or by topical route, eg in the form of ointments, creams or oils. Is Preferred oral administration.

The production of pharmaceutical preparations can be done in a way that will be familiar to any subject matter expert, which consists of incorporating the com

described positions of the formula I and / or its pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, to a form of galenic administration together with solid support materials or liquid, suitable, non-toxic, inert, therapeutically compatible, and, if desired, with pharmaceutical adjuvants usual.

The ideal support materials are not only those inorganic support materials, but also the materials organic support For example, they can be used as support materials for tablets, coated tablets, dragees and Hard gelatin capsules lactose, corn starch and its derivatives, talc, stearic acid and its salts. The Support materials suitable for gelatin capsules soft are, for example, vegetable oils, waxes, semi-solid and liquid fats and polyols (however, depending on the nature of the active ingredient may that the use of supports is not necessary in the case of soft gelatin capsules). The ideal support materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. The Support materials suitable for injectable solutions they are, for example, water, alcohols, polyols, glycerin and vegetable oils. The ideal support materials for suppositories are, for example, natural or hydrogenated oils, waxes, fats and semi-liquid polyols and liquids Suitable support materials for topical preparations are glycerides, semi-synthetic glycerides

Ethics and synthetics, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and derivatives of cellulose. As pharmaceutical adjuvants, the usual stabilizers, preservatives, humectants and emulsifiers, the agents that improve consistency, the aroma, the salts to vary the osmotic pressure, the buffer substances, solubilizers, dyes and masking agents as well as antioxidants.

The dosage of the compounds of the formula (I) may vary within wide limits depending on the disease to be controlled, the age and individual health status of the patient and the mode of administration and obviously will have to meet the individual requirements in each particular case. For adult patients a daily dosage of 1 to 1000 mg is taken into consideration, especially 1 to 100 mg Depending on the dosage it is convenient administer the daily dose divided into several units of dosage, eg in 1-4 sub-dose.

The compounds of the invention are useful with preference for the treatment of diseases and disorders which are modulated with A2B receptor antagonists. Such diseases and disorders include, for example, diabetes Type 2, diseases characterized by growth abnormal blood vessels, such as diabetic retinopathy, asthma, bronchospastic and allergic diseases as well as other obstructive diseases of the

respiratory tract and inflammatory disorders of the tract gastrointestinal, including diarrhea.

The invention also relates to compositions Pharmaceuticals that contain a receptor antagonist A2B, already defined before, and a pharmaceutically acceptable carrier and / or adjuvant.

The invention also encompasses receptor antagonists. of A2B already described above for use as substances therapeutically active, especially as substances therapeutically active intended for treatment and / or prophylaxis of diseases that are modulated with antagonists of the A2B receptor, in particular as therapeutically active substances for the treatment and / or prophylaxis of type 2 diabetes, diabetic retinopathy, asthma, bronchospastic and allergic diseases, disorders inflammatory of the gastrointestinal tract and diarrhea.

The invention also relates to a method for therapeutic and / or prophylactic treatment of diseases that they are modulated with A2B receptor antagonists, in particular for the therapeutic or prophylactic treatment of type 2 diabetes, diabetic retinopathy, asthma, bronchospastic and allergic diseases, disorders inflammatory of the gastrointestinal tract and diarrhea said method consists of administering a receptor antagonist A2B already defined before a human being or an animal.

The invention also encompasses the use of antagonists of A2B receptor already defined before for treatment therapeutic and / or prophylactic diseases that are modulated

with A2B receptor antagonists, in particular for the therapeutic and / or prophylactic treatment of diabetes type 2, diabetic retinopathy, asthma, diseases bronchospastic and allergic, inflammatory disorders of the gastrointestinal tract and diarrhea.

The invention also relates to the use of antagonists. of the A2B receptor already described above for the manufacture of drugs intended for therapeutic treatment and / or prophylactic type 2 diabetes, retinopathy diabetic, asthma, bronchospastic diseases and allergic, inflammatory disorders of the gastrointestinal tract and diarrhea. Such medications contain an A2B receptor antagonist already described above.

Type 2 diabetes is the preferred disease that can deal with the A2B receptor antagonists of the present invention

In the following reaction scheme and description attached the general methodology for obtaining of the new compounds of the present invention.

The ureas of the formula I, in which X = N or C, can obtained by reacting the corresponding thiazolo-pyrimidine / pyridine-amine 2 with several amines using methods standard. For example, pyrimidine / pyridine-amine 2 can become “in situ” in the corresponding carbamoyl derivative using triphosgene or phosgene, which is then made react with the amine of interest. They can also be used the phenyl carbamate derivatives corresponding to the

thiazolo-pyrimidine / pyridine-amines 3 for reaction with the substituted amines in various ways (scheme 1).

Scheme 1

image16

image17

3 bX = C

i) triphosgene / phosgene, (R3) (R4) NH; ii) (R3) (R4) NH, acetonitrile at reflux,

iii) phenoxycarbonyl chloride

5 The synthesis of the previous compounds amine 2, which can be used to obtain the compounds of the formula I, are represented in schemes 2-6. In scheme 2 you illustrates the synthesis of thiazolopyrimidine-amines 2a, in which R2 is H. These compounds are easily obtained at

10 starting from 4,6-dichloro-5-amino-pyridine (commercial product) in three simple chemical reactions, which involve the condensation with benzoyl isocyanate, a hydrolysis of benzoyl group catalyzed with a base and a reaction of chlorine displacement with lower alkyl alkoxides

15 corresponding to R1.

Scheme 2

image5 Cl image5 image5 image5 image5 image5 image5 R1

Or Cl

NH2 ON image5 NN

i, ii

iii NN

N

+ NH2NH2

N Cl

S NSN

2nd

i) condensation, ii) hydrolysis, iii) alkoxide displacement

The compounds of the formula 2a, in which R2 is uncle

5 lower alkyl ether can be obtained in the manner shown in scheme 3. The sequence starts with nitration of 2-lower alkyl-thienyl-4,6-dihydroxy-pyrimidine. The appropriately substituted lower alkylthio pyrimidines they can be easily obtained according to methods of the

10 technical bibliography (see eg, J. Med. Chem. 27 (12), 1621-9, 1984; international patent application PCT 2001/092263, 06 December 2001; J. Het. Chem. 41 (4), 581-585, 2004), which It can be nitrated under standard conditions. The nitrated pyrimidine derivative can be chlorinated with reagents of the penta type

15 phosphorus chloride. The thiocyanate group and several alkoxides of Lower alkyl can be introduced thanks to the displacement of chlorine, successively. The desired molecules of formula 2a can be obtained through a reaction thiazole formation standard, that is, the reduction of

20 nitro to amine group, which undergoes easy cyclization, to get the thiazole ring.

Scheme 3

image5 OH image5 OH image5 Cl NO2

image18 NO2 image5

iii

i

N

N

N

SNOH R18SNOH SNCl

R18

R18

image5 Cl image5 R1 image5 R1 NO2

NO2 saw

N image5

iv, v N

N

N

NH2 SNSCN R18SNSCN SN

S

R18

R18

2nd

R18 = lower alkyl

i) nitration, ii) chlorination, iii) thiocyanate displacement, iv) displacement with lower alkyl alcohol, v) reduction of the nitro group, vi) cyclization

The compounds of the formula 2a, in which R2 is a lower alkyl ether or a hydroxy group, can be obtained 5 as represented in scheme 4. The sequence starts with the protection of the 2-amino group of the compound of the formula 2a, wherein the group R2 is an alkyl thioether lower. The pyrimidino-thiazole compound with the 2-amino group protected can be oxidized then applying methods 10 thioether oxidation standard to obtain the corresponding alkyl sulfone derivative. Then you can scroll to the alkyl sulfone with a lower alkyl alkoxide or a hydroxide and the deprotection of the amide will allow to obtain the desired molecules of the formula 2a, in which the group

R2 is a lower alkyl ether or a hydroxide (see e.g. Bioorganic & Medicinal Chemistry Letters 12 (1), 81-84, 2002; Tetrahedron 56 (27), 4739-4745, 2000).

Scheme 4

image5 R1 image5 image5 image5 R1 NN image5 N iNNH2 NHP

H.H

S N SN

R18R18

image19

2nd

R18 = lower alkyl image20 R1 image5 R1 N image5 iii

N image5

N NHP

NH2R18

S

S R2 N O

OR

2nd

R2 = lower alkoxy, hydroxy

i) protection of the amine, ii) oxidation of the alkylthio group, iii) displacement with lower alkyl alkoxides or hydroxide

The compounds of the formula 2b, (X = C) in which R2 is H, are obtained in the manner represented in scheme 5. The 5 sequence begins with the displacement of bromine from 4-bromo-3-nitropyridine with lower alkyl alkoxides and then the resulting pyridine derivative is reduced and chlorinated applying the standard conditions. 4-Alkoxy-3-amino-2-chloropyridine can be heated to reflux in a solvent

10 suitable in the presence of ammonium thiocyanate, obtaining compounds of the formula 2b, wherein R2 is H.

Scheme 5

image5 Br

image5 R1

NO2 i

NO2

ii, iii

N N

image21

2b

i) displacement with lower alkyl alkoxide, ii) reduction (from nitro to amino), iii) chlorination, iv) condensation with ammonium thiocyanate and cyclization

The compounds of the formula 2b, wherein R2 is a thioether group of lower alkyl, lower alkyloxy or 5 hydroxy can be obtained in the manner indicated in scheme 6. The sequence starts with etherification and esterification simultaneous chelidamic acid an alkyl alcohol lower appropriate in acidic conditions, similar to described by Inouye et al. (J. Amer. Chem. Soc. 117, 1241610 12425, 1995). Then the ether / diester of resulting pyridine in the corresponding 2,6-dibromopyridine derivative by successive hydrolysis, with a subsequent reaction of Hunsdieker modified by Barton (Barton et al., Tetrahedron, 41, 3901-3924, 1985). He Dibromo-pyridine derivative can be nitrated under conditions nitration standard obtaining the corresponding nitro-pyridine derivative, from which, applying a series of reactions similar to that described in the previous Schemes 3 and 4, the compound of the formula can be obtained

2b, wherein R2 is lower alkyl thioether, (alkyl lower) -sulfone, lower alkyloxy or hydroxy. Scheme 6

image22 R1

image5 OH image5 R1 ii, iii

i Br NBr

HOOC N COOH ROOC N COOR

image23 R1

NH2 Br

NH2

OO

2b 2b

R2 = OH or lower alkyl alkoxy R18 = lower alkyl

i) esterification and etherification with lower alkyl alcohols, ii) hydrolysis of the esters, iii) Barton's modified Hunsdiecker reaction, iv) nitration, v) condensation with ammonium isothiocyanate, vi) displacement with lower alkyl thiolate, vii) oxidation of thio-ether, viii) lower alkyl alkoxide or hydroxide displacement

5 The compounds of the formula I, in which the R3 groups and R4 can join to form rings of 5 or 6 links with various substituents The 6-link amines, which they include a nitrogen atom, they can be a ring of piperazine The compounds of the formula I, which contain a

10 piperazine ring, can be obtained by performing reactions indicated in scheme 7, through the compound intermediate 4.

Scheme 7

image5 R1

image5 R1 N image5 HX N image5 N image5 i, ii XS

NH2 R2 NN image5 image5 NH

S

R2 N O 4 aX = N

2 aX = N 4 bX = C 2 bX = C O ArylR2

image24

6 to X = N; n = 0, 1 7 to X = N; X = CO or SO2; n = 0, 1 6 b X = C; n = 0, 1 7 b X = C; X = CO or SO2; n = 0, 1

i) condensation (see scheme 1) with Boc-piperazine, ii) TFA or HCl, iii) reductive amination with 5 (R19 = H, lower alkyl or caboxyalkyl, hydroxy-alkyl), iv) co-condensation with aryl-alkyl chloride sulfonyl

The compounds of formula 6, wherein R19 is H or a lower alkyl or substituted alkyl group, can be obtained 5 applying reductive amination techniques, this is done react the aryl- or heteroaryl-aldehyde or ketone timely substituted with intermediate compounds 4 and be reduce piperazine "in situ" with a reducing agent, by example sodium cyanoborhydride. The intermediate compounds of 10 formula 4 can be easily obtained by the series of reactions represented in scheme 1. The compounds of Formula 7, whose nitrogen from position 4 of the piperazine is substituted by several acyl and sulfonyl groups,

can be easily obtained by reaction of the halides of

acyl or sulfonyl with piperazine-ureas 4. In addition, compounds of the formula 6 can also be obtained by following reactions, represented in scheme 8, in the that properly substituted piperazines can with

5 pour into the desired compounds directly by reaction with thiazolo-pyrimidine / pyridine-amines 2 applying the series of reactions described in scheme 1.

Scheme 8

image5 R19

image5 R19

i

Aryl

image5 NH

Aryl image5 ii

n

N

n

N

image5 ON

HN

image5 ON

OR

OR

i) reductive amination, ii) HCl or TFA

10 The compounds of the formula I can be obtained in the that groups R3 and R4 can join to form a ring of piperazine, whose distal nitrogen is substituted with groups aralkyl in alpha position. These groups can be an ester, 15 or hydroxy-methyl or (lower alkoxy) methyl (compounds 9, 10 and 11, respectively). These compounds can be obtained with according to scheme 9, carrying out well known reactions.

Scheme 9

image5 image25 OH

image26 COOR

image5 NH

i

Aryl

Aryl

PN

PN

PN

iv

iii

image5 R1 N image5

H

X

OR21

image5 COOR20

N image5

SN image5 image5 N

R2 N

image27 Aryl

Aryl

OR

9a X = N image5 R1 9b X = C iv N image5

H

X

image5 OH S image5 N image5 image5 N

N

R2 N O Aryl

10 a X = N 10 b X = C

image5 R1 N image5 Hx

N image5 image5 OR21 S NN

R2 N O Aryl 11 a X = N 11 b X = C

i) alkylation with an α-bromoarylacetic acid ester (R20 = lower alkyl), ii) reduction, iii) O-alkylation (R21 = lower alkyl) iv) see scheme 1

Compounds 12 of formula I, wherein R3 and R4 are

5 join to form the 6-link piperidine ring, they can Obtained from easily available reagents. The Properly substituted piperidines can be obtained by applying methods from the technical literature, for example, amides and amino-alkyl derivatives can be obtained at

10 from 4-amino-piperidine easily obtainable by condensation reactions with an aryl carboxylic acid ade

cuado and reductive amination, respectively. Similarly, piperidines linked to ether and sulfonyl groups can Obtained from 4-hydroxy-piperidine, by substitution reaction with an aryl alkoxide or a thio5 aryl alkoxide and subsequent oxidation to sulfone, respec

tively. Piperidines bound to can be obtained by methods of the using 4-benzyl-piperidinone and Tiles of aril-Grignard (scheme 10).

Scheme 10

through a carbon organometallic chemistry his reaction with reac-

image5 image5 Xi image5 W

Aryl image5 OR image5 N

OR NOT

image19

O A = CHO, OH, NH2 W = CHOH, O, SO2, NHCO, NHCH2

W = CHOH, O, SO2, NHCO, NHCH2 W = CHOH, O, SO2, NHCO, NHCH2

i) a) aryl-Grignard reaction, if A = CHO or b) Mitsunobu reaction with hydroxy-aryl compounds, if A = OH; or c) reductive amination with aryl methyl amines if A = NH2; d) formation of amide with aryl carboxylic acids, if A = NH2, e) if A = OH is converted to OMs, then reacts with aryl alkyl thiols and thioethers are oxidized to sulfones ii) HCl or TFA

Compounds 14 of formula I, in which the groups R3 and R4 join to form a piperidine ring, which is 15 replaced in position 4 by ureas and cyclic carbamates benzo-fused, can be obtained by general methods described above (see scheme 1) using derivatives

image28

Suitable piperidine. Piperidines 13 with cyclic urea benzo-fused in position or with carbamates can be obtained by a reaction from Mitsunobu (J. Med. Chem. 47 (27), 6921, 2004) between benzo-fused cyclic ureas or carbamates 5 suitably substituted and 4-hydroxy-piperidine. These compounds can also be obtained from a derivative of 4-amino-piperidine appropriately substituted by a nucleophilic displacement of o-nitro-halo-benzenes, which then they are reduced and cycled as indicated in the scheme 10 11 (J. Med. Chem. 57 (6), 814, 1987; Tetrahedron 57 (6), 981, 2001). Benzofused cyclic ureas obtained from of 1,2-diaminobenzenes and benzofused cyclic carbamates obtained from o-hydroxy-2-aminobenzenes, can be obtained by applying methods from the technical literature

15 (Pharmaco. 60 (2), 127, 2005; Nuclear Medicine Communications 25 (8), 845, 2004; J. Amer. Chem. Soc. 77, 5757, 1955; Green Chemistry 6 (2), 78, 2004; J. Amer. Chem. Soc. 71, 1265, 1949).

Scheme 11

OR image5 if AY = OH HN image5 N

image29 R23 PN image5 Y

R24 12 Y = OH, or NH2 13 A = NH, NH-R22 image5 vi P = protective group (R22 = lower alkyl) or OP = protective group

image5 image5 R1 if iii Y = NH2

image30 N image5 image5 OR image5 HX N AS NNR2 N R24 O image5 NO2H

image5 N R24 R23 PN 14 at X = C; A = A = NH, NH-R22 R23

(R22 = lower alkyl) or O 14 b X = N; A = NH, NH-R22 (R22 = lower alkyl) or O

i) benzo-fused cyclic urea (R23 = R24 = independently H or lower alkyl, lower alkoxy or halogen) Mitsunobu reaction, ii) deprotection, iii) substitution reaction with an o-halo-nitro-benzene, iv) reduction with Ni Raney, v) phosgene, vi) see scheme 1

Compounds 15 of formula I, in which the

R3 and R4 groups join to form a piperidine ring,

5 which is substituted in position 4 by cyclic amines or

acyclic, can be obtained from the intermediate compound

4-piperidinone 16, applying standard procedures of

reductive amination (scheme 12).

Scheme 12

image5 OR image5 OR

i, ii

N

O n

image31

Cl image5 R1

image5 R1 N image5 HX N image5 N image5 Hiv X

image5 N image5 image5 R25 SN image5 OR

R2 NSN image5 N image5 R2 N

O O R26

16 aX = N 15 aX = N 16 bX = C

15 bX = C i) Pd-C / H2, ii) triphosgene, iii) condensation with 2, iv) reductive amination with HN (R25) (R26)

Compounds 17 of formula I, wherein R3 and R4 are

5 join to form a piperidine ring, which is substituted in position 4 by a carbinol and an aryl group, they can Obtained from intermediate compounds 16 or starting from a 4-piperidone derivative protected by an addition of Grignard, as indicated in scheme 13

10 (see for example, Eur. J. Med. Chem. 40 (12), 1197, 2005; Bioorg Med. Chem. Lett. 15 (7), 1891, 2005; Eur. J. Med. Chem. 10 (2), 178, 1975).

Scheme 13

image5 R1 image5 R1

N image5 HX N image5 Hxn image5

i

image5 N image5 image5 OH S

R2 NN image5 Or SN

R2 NO OR Aryl

16 aX = N 17 aX = N 16 bX = C 17 bX = C

image32

P = protecting group i) Grignard reaction with aryl magnesium halide, ii) deprotection

The compounds of the formula I, in which the R3 groups and R4 bind to form a piperidine ring, which is 5 replaced in position 4 by an aryl group and several groups functional bonded by a carbon, for example the cyano 18 derivatives, hydroxy methyl 19, ester 20, acid carboxylic 21 or amide 22, can be obtained from a 4-cyano-4-arylpiperidine derivative protected according to 10 well-known reactions, which are represented in the scheme

14. 4-Cyano-4-arylpiperidine derivatives can be easily obtained by applying methods already described in the technical literature (see, for example, J. Med. Chem. 48 (5), 1336, 2005; Bioorg Med. Chem. Lett. 14 (1), 207, 2004;

15 Bioorg. Med. Chem. 12 (19), 5063, 2004; Tetrahedron 60 (22), 4875, 2004; Bioorg Med. Chem. Lett. 11 (14), 1959, 2001; European patent application 924196, June 23, 1999; Org.

Prep. and Proc. Int. 28 (4), 478, 1996; J. Heterocycl. Chem 23 (1), 73, 1986).

Scheme 14

CN

CONHR27

R2 COOH Aryl

image33

=

i) lower alkyl alcohololysis, acid (R20 = lower alkyl); ii) check out, =

iii) see scheme I, iv) hydrolysis, v) amide formation (R27 = lower alkyl)

5

Compounds 23 of formula I, in which the groups R3 and R4 join to form a piperidine ring, which passes to be part of the spiroindoline ring, can be obtained from the appropriate spiroindoline-piperidines 10 applying a reaction scheme similar to that described above (see scheme 1). Spiroindoline-piperidines can get

image34

using methods described in the technical literature, for example starting from aryl hydrazines and 4-formyl piperidines (see WO 96/33189; US 5723616, 1998; Tetrahedron Lett. 38 (9), 1497, 1997) (scheme 15).

5 Scheme 15

23 bX = C

i) Toluene at reflux, (R28 = R29 = independent. H or lower alkyl, lower alkoxy or halogen (hydrazone formation), ii) CF3COOH (Fischer indoles synthesis), iii) NaBH4 (imine reduction), iv ) alkylation (R22 = lower alkyl), v) deprotection, vi) see scheme 1

The compounds of the formula I, in which the R3 groups and R4 bind to form a piperidine or 3,6dihydro-2H-pyridine ring, which is substituted by an aryl group

10 in position 4, compounds 24 and 25 respectively, can Obtained from intermediate 17, which they can be dehydrated using an acid catalyst, obtaining the compounds of the formula 24. The compounds of Formula 24 can be hydrogenated by applying methods of

Pd catalyzed hydrogenation, obtaining the compounds of formula 25, as indicated in scheme 16.

The compounds 21 of the formula I, in which the groups R3 and R4 join to form a piperidine ring that is bis-hydroxylated and has an aryl substituent in the position 4, can be obtained conveniently from the

5 compounds of the formula 24 by a bishydroxylation reaction, as indicated in scheme 16. Scheme 16

R1

R2

Aryl

Aryl

image35

25 aX = N 26 aX = N 25 bX = C 26 bX = C

i) dehydration, ii) hydrogenation, iii) bis-hydroxylation (OsO4 / NaIO4 or epoxidation followed by the opening of the ring catalyzed with a base)

The compounds 27 of the formula I, in which the groups R3 and R4 bind to form a 3-benzyl-piperidine ring, can be obtained through the reactions represented in the Scheme 17. The 3-benzyl-piperidines necessary for this they can be obtained from pyridine-3-carboxaldehyde and

15 reagents of aril-Grignard. The resulting carbinoles can deoxygenated and the pyridine ring can become saturated performing a catalytic hydrogenation, which they have described B.

image36

Agai et al. (Tetrahedron 59, 7897-7900, 2003). 3-Benzylpiperidines can react easily with pyrimidine / pyrimidine-amines 2, as described above (see scheme 1) to obtain the compounds of the formula I.

5 Scheme 17

image5 R1 N image5

H

X

N image5 SN image5

R2 N

OR 27 to X = N

Aryl

27 bX = C

i) aryl-Mg halide, ii) hydrogenation, iii) see scheme 1

Compounds 28 of formula I, in which the groups R3 and R4 join to form a piperidine ring, which is 10 substituted by a 4-N-acetyl-4-aryl group, can be obtained from the compounds of the formula 17 applying a addition of acid catalyzed acetonitrile, then hydrolyzes the resulting adduct, obtaining the compounds of formula 28 (scheme 18). A similar reaction with Chloro-acetonitrile allows to obtain the intermediate compound 29, which can become the corresponding derivative amine 30. Thus, the compounds of the formula 30, in which the amine may be alkylated with a lower alkyl 33 o (lower alkyl) acylated 32 o (lower alkyloxy) car

20 bonilada 31, as indicated in scheme 18.

Scheme 18

image5 R1 image5 R1

N image5 Hx image5 Cl ON image5 image5 OH ii N image5 H

X

SN N image5 R2 N NH Aryl O SN

R2 N 17 aX = N O Aryl 17 bX = C

29 aX = N 29 bX = C

i image5 R1

image31

image5 R1 image5 OR

N image5

H

X

N HX N image5 NH2 30 aX = NN image5 NH SN

R2 N

30 bX = C SNR2 N Aryl OAryl O

28 aX = N 28 bX = C

image5

image5 R1

image5 OR OR31 N image5

H

X

N image5

NH

SN

R2 N Aryl

OR

image5 R1 N image5 image5 image5 R26

image22

H

X

N

NH v

SN

R2 N Aryl O

33 aX = N 33 bX = C

31 aX = N image5 R1 image5 R30 31 bX = C

image5 Y

N image5 H

N image5 X

NH SN

R2 N Aryl O

32 to X = N; Y = CO or SO2 32 b X = C; Y = CO or SO2

i) CH3CN / H2SO4 / AcOH, ii) ClCH2CN / H2SO4 / AcOH, iii) thiourea / EtOH / AcOH / HCl, iv) reductive alkylation with R26-CHO (R26 = lower alkyl), v) acylation with R30-CO-Cl

or R30-SO2-Cl (R30 = lower alkyl) vi) R31-OCO-Cl, base (R31 = lower alkyl)

The compounds of the formula I, in which the R3 groups and R4 bind to form a 1,3,8triaza-spiro ring system [4,5] decan-4-one and give rise to the compounds of formula 34 and 35, can be easily obtained by Strecker type synthesis from 4-piperidinone

protected, as indicated in scheme 19, according to the technical literature (WO 2005/040166; J. Med. Chem. 28 (12), 1811, 1985; US 199,142, 1982).

Scheme 19

image37

R32

Aryl

35 aX = N 35 bX = C

i) synthesis of Streckerii) triethyl orthoformate, iii) alkylation (R32 = lower alkyl group), iv) deprotection, v) see scheme 1.

5

Compounds 36 of formula I, in which the groups R3 and R4 bind to form a 3-benzyl-pyrrolidine, they can Obtained from lactam derived from phenylglycinol 10 (Meyers, A.I. et al., J. Org. Chem. 54, 4243, 1989), as indicated in scheme 20, according to the synthesis method

described by Westrum and Meyers (Tetrahedron Lett. 973-976, 1994). Scheme 20

image5 H image5 HH OO

Aryl N N ii, iii

i OR

OR

image5 R1 image5 H

N image5 HN image5 iv X

Aryl N

SN image5 R2 N

H Aryl O

36 aX = N 36 bX = C

i) LiHMDS, aryl halide alkylation-CH2, ii) reduction with LAH, iii) hydrogenation,

iv) see scheme 1

5

Similarly, compounds 37-39 of formula I can be easily obtained, in which groups R3 and R4 bind to form a 3-amino-, 3-amido- or 3-sulfonamidopyrrolidine, can be easily obtained from

10 3-amino-pyrrolidine derivatives that are commercial products (scheme 21).

Scheme 21

R1

HN

NH-P

Aryl

image38

39 to X = N; Z = CH2 or (CH2) 2-3-O39 b X = C; Z = CH2 or (CH2) 2-3-O

i) see scheme 1, ii) deprotection, iii) acylation or sulfonylation, iv) alkylation

Compounds 40 of formula I, in which the rest R3 is lower alkyl or hydrogen and R4 is lower alkyl 5 substituted by aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino or aroylamino, can be obtained from of suitably substituted amines by performing a series of reactions indicated in scheme 1. These amines secondary, provided with different substituents, can

10 Obtained by applying standard methods of synthesis.

image5 R1 see scheme 1 N image5

R3 image5 image5 R4 XH

NN image5 image5 image5 R3 H SNR2 N

Or R4

40 aX = N 40 bX = C

Compounds 41 of formula I, in which the groups R3 and R4 join to form a substituted morpholine ring by aryl in position 3, can be obtained from 3

5 appropriately substituted aryl-morpholines, which in turn can be obtained by methods already described in the bibliography technique. For example, a series of reactions, which starts from easily accessible aryl-epoxides has been proposed by Epifani, E. et al. (J. Med. Chem. 26, 254-259, 1983), may

10 be performed to obtain 3-aryl morpholines properly replaced (scheme 22).

Scheme 22

Aryl

OR

image39

41 to X = N; Y = O, S 41 b X = C; Y = O, S

i) ammonia, ii) N-acylation, iii) cyclization, iv) reduction, v) see scheme 1, vi) methanesulfonyl chloride, base, vii) displacement with potassium thioacetate, viii) catalyzed hydrolysis with thioacetate base and cyclization

Compounds 42, 43 and 44 of formula I, in which groups R3 and R4 join to form derivatives of 5 ring 2,5-diaza- [2.2.1] -bicycloheptane substituted in position 5, can be obtained from 2,5-diaza- [2.2.1] bicycloheptanes properly substituted in position 5 and 2,5-diaza- [3.3.0] -bicyclooctanes substituted in position 5, which can be easily obtained using reagents eat

10 ciales and applying the methods already described above (see scheme 1).

image40

image41

image42

Compounds 46 of formula I, in which the groups R3 and R4 join to form a 3-benzyl-3 derivative

substituted carboalkoxy-piperidine, can be obtained from of the corresponding 3-benzyl-3-carboalkoxy-piperidines, performing the series of reactions represented in the scheme

1. 3-Benzyl-3-carboalkoxy piperidines can be obtained 5 according to the procedures described by Maligress,

P.E. et al. (J. Org. Chem. 63, 9548, 1998).

image43

46 a X = N, R20 = lower alkyl 46 b X = C, R20 = lower alkyl

Compounds 47 of the formula I, in which the groups R1 and R2 join to form 1-aryl-3,8-diaza10 spiro [4,5] decan-4-one derivatives, can be obtained from the corresponding 1-aryl-3,8-diazaspiro [4,5] decan-4-ones, performing the sequence of reactions represented in the Scheme 1. The 1-aryl-3,8-diazaspiro [4,5] decan-4-ones can Obtained by the procedures described by Van Parys, M. 15 et al. (Bull. Des Soc. Chimiques Belges 90, 757, 1981) or Galley, G. et al., (WO 01/94346 A1, 2001). Similarly, the compounds of formula 48 can also be obtained at from the appropriate piperidine compounds (see Tetrahedron Lett. 43 (38), 6865, 2002; Helv. Chimica Acta

20 83 (6), 1247, 2000; European patent application 636609, nineteen ninety five).

image44

image45

Or Aryl

47 to X = N, R34 = H or alkyl inf. 47 b X = C, R34 = H or alkyl inf.

Compounds 49 of formula I, in which the groups R3 and R4 bind to form substituted pyrrolidine derivatives in position 3, can be obtained from the

5 corresponding substituted pyrrolidines in position 3, carrying out the series of reactions represented in Scheme 1. Pyrrolidine derivatives substituted in position 3 are easily obtained from 3-hydroxy

pyrrolidine, applying

methods already acquaintances from the technique

(see e.g.

Alanine, TO. Y cabbage., WO 01 / 81303A1, 2001; Y

Sternfeld et al., J. Med. Chem. 42, 677-690, 1999).

image46

49 to X = N; Z = O or SO2; Ar = aryl or aralkyl 49 b X = C; Z = O or SO2; Ar = aryl or aralkyl

The following examples are provided to illustrate the preferred embodiments of the present invention, but This is not intended to limit the scope of the invention.

Example 1

Synthesis of 4- (3-Trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide.

image5 Cl image5 OR image5 Cl image5 OR

NH2 N

N acetone

N N

+

N

H

N Cl SNS

5

Step 1: A mixture of 5-amino-4,6-dichloro-pyrimidine (5.0 g, 30.49 mmol) and acetone (30 ml) is treated at 25 ° C with benzoyl isothiocyanate (5.5 g, 33.54 mmol). It shakes

10 the mixture at reflux for 6 h and then cooled to 25 ° C. The resulting solids are collected by filtration, washed with acetone and petroleum ether and dried under vacuum, obtaining the N- (7-chloro-thiazolo [5,4-d] pyrimidin-2-yl) benzamide (7.87 g, 79%) in the form of a matt white solid. He

15 NMR spectrum obtained from the sample is compatible with the compound structure

image47

Step 2: A mixture of N- (7-chlorothiazolo [5,4-d] pyrimidin-2-yl) -benzamide (1.0 g, 3.06 mmol) is treated at 25 ° C 20 and methanol (25 ml) with sodium methoxide (1.65 g, 30.60 mmol). The mixture is stirred at reflux for 3 d. Then you Concentrate the reaction mixture under vacuum. It dissolves on

resulting solid in ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated in vacuo, obtaining 7-methoxy-thiazol [5,4-d] pyrimidin-2-ylamine

5 (385 mg, 70%) as a slightly yellow solid. He NMR spectrum obtained from the sample is compatible with the compound structure

image48

Step 3: a solution of piperazine-1 is treated at 0 ° C

10 tert-butyl carboxylate (4.0 g, 22 mmol) in methylene (40 ml) with pyridine (2.65 ml, 33 mmol) and triphosgene (3.2 g, 10.8 mmol). The solution is stirred resulting yellow at 25oC for 1 h. Then you divide the reaction mixture between methylene chloride (200

15 ml) and a 1N aqueous solution of hydrochloric acid (75 ml). Be Dry the organic phase with magnesium sulfate and concentrate under vacuum, obtaining tert-butyl 4-chlorocarbonyl-piperazine-1 carboxylate (4.73 g, 89%) as a solid yellow. This material is used in the next step without

20 more purification.

image49 OR

OR image50 OO

N

N

H

N

image5 OR

N image5

NH2

+

Cl

S SN image5 image5 N

N

OR

OR

OR

Step 4: a solution of 7-methoxythiazolo [5,4-d] pyrimidin-2-ylamine (3.5 g, 19.2 mmol) is treated at 25 ° C 5 tetrahydrofuran (100 ml) with sodium hydride (60% in mineral oil, 2.3 g, 57 mmol). It shows a slight gas evolution The purple suspension is heated resulting at 50oC for 1 h. Then the Reactant mixture at 25 ° C and treated with N, N-diisopropyl 10 ethylamine (10 ml, 57 mmol). The resulting mixture is stirred at 25oC for 30 min. The mixture is treated with a solution of Tert-butyl 4-chlorocarbonyl-piperazine-1-carboxylate (4.73 g, 19 mmol) in tetrahydrofuran (20 ml) over a period 10 min. The reaction mixture is stirred at 50 ° C for one 15 night The reaction mixture is then concentrated with vacuum, diluted with methanol (100 ml) and absorbed on gel of silica (6 g). The silica gel is divided into two batches same. By ISCO chromatography (330 g, silica gel, gradient elution 5/95 methanol / methylene chloride) is

20 obtains tert-butyl 4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazine-1-carboxylate (5.58 g, 74%) in the form of a matt white solid; EM-LR of C16H22N6O4S (M + H) + a m / z = 395. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

image51

OR

Or HCl

N image5 H HHCl (g) O

N image5 SN image5 image5 NH OO

OR

Step 5: Bubble at 0 ° C for 10 min on gaseous hydrogen chloride through a solution of 4

5-Methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazine-1-carboxylic acid tert-butyl ester (5.20 g, 13 mmol) in chloride of methylene (70 ml). A white precipitate forms. It shakes the resulting suspension at 25 ° C for 2 h. Then the mixture is concentrated under vacuum and dried under high vacuum,

10 obtaining the piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride (4.61 g) as a white solid; EM-LR of C11H14N6O2S (M + H) + at m / z = 295. This solid is used in the next step without further purification.

image5 OR image5 image5 image5 image5 OR image5 HCl

N

N DIEA

H NN Hmethanol N

N image5 S NNH SN image5 NN

N

FO

O F F

fifteen

Step 6: A solution of the (7methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide hydrochloride of piperazine-1-carboxylic acid (2 g, 6.0 mmol) in methanol (200) is treated ml) with

20 N, N-diisopropylethylamine (2.2 ml, 12.6 mmol). Stir the

mix at 25oC for 10 min until a solution forms

transparent. Thereafter the reaction mixture is treated. with acetic acid (1.75 ml, 30.6 mmol), 3-trifluoromethylbenzaldehyde (2.4 ml, 17.9 mmol) and sodium cyanoborhydride (1.1 g, 17.7 mmol). This mixture is stirred at 25 ° C for one 5 night The reaction mixture is concentrated under vacuum and partition between methylene chloride and an aqueous phosphate buffer (pH = 7). The organic phase is washed with an aqueous solution. saturated with sodium chloride, dried with magnesium sulfate, dried filter and concentrate under vacuum, obtaining a solid. Be 10 dissolves this solid in methanol and is absorbed on gel silica (4 g). By ISCO chromatography (330 g, silica gel, gradient elution 5/95 methanol / methylene chloride) is obtains (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide from 4- (3-Trifluoromethyl-benzyl) -piperazine-1-carboxylic acid

15 (1.56 g, 58%) as a white solid; EM-LR of C19H19F3N6O2S (M + H) + at m / z = 453. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

In a similar way the compounds of the Examples 2-28 as follows: 20 Example 2

image52

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

4- (3-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide is obtained as a white solid; EM-LR of C18H19ClN6O2S (M + H) + at m / z = 419. The NMR spectrum obtained from

5 the sample is compatible with the structure of the compound. Example 3

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

4- (4-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide is obtained as a white solid. ; EM-LR of C18H19ClN6O2S (M + H) + at m / z = 419. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

15 Example 4

image52

image53

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 3-Cyano-benzaldehyde is obtained 4- (3-cyano-benzyl) -pipe (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide

5-razine-1-carboxylic acid in the form of a white solid; EM-LR of C19H19N7O2S (M + H) + at m / z = 410. The NMR spectrum obtained from the Sample is compatible with the structure of the compound. Example 5

image52

10 From the piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 4- (2-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide is obtained as a white solid; EM-LR of

C18H19ClN6O2S (M + H) + at m / z = 419. The NMR spectrum obtained from The sample is compatible with the structure of the compound. Example 6

image54

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 4- (3-Methoxy-benzyl) (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide 3-methoxy-benzaldehyde

5 piperazine-1-carboxylic acid in the form of a white solid; EM-LR of C19H22N6O3S (M + H) + at m / z = 415. The NMR spectrum obtained of the sample is compatible with the structure of the compound.

Example 7

image5 ON

N H

N image5 SN image5 N

NO F

F

10 From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 3,4 (3,4-Difluorbenzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained in the form of white solid;

15 LRMS of C18H18F2N6O2S (M + H) + at m / z = 421. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 8

image5 ON

NH

N image5 SN image5 N

N O Cl

OR

image5

From the hydrochloride of (7-methoxy-thiazolo [5.4

d] piperazine-1-carboxylic acid pyrimidin-2-yl) -amide and

5-Methoxy-4-methoxy-benzaldehyde is obtained (7-methoxy

4- (3-Chloro-4 acid thiazolo [5,4-d] pyrimidin-2-yl) -amide

methoxy-benzyl) -piperazine-1-carboxylic powder

White; LRMS of C19H21ClN6O3S (M + H) + at m / z = 449. The

NMR spectrum obtained from the sample is compatible with the 10 structure of the compound. Example 9

image5 ON

NH

N image5 SN image5 N

N OR

image5 OR

+

N image5 OR

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 4- (3-Nitro-benzyl acid) (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide is obtained from 3-nitro-benzaldehyde

piperazine-1-carboxylic in the form of white powder; EM-LR of C18H19N7O4S (M + H) + at m / z = 430. The NMR spectrum obtained from the Sample is compatible with the structure of the compound.

Example 10

image55

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and Methyl 3-formyl benzoate gives 3- [4- (7-methoxythiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-ylmethyl]

10 methyl benzoate in the form of a white solid; EM-LR of C20H22N6O4S (M + H) + at m / z = 443. The NMR spectrum obtained from the Sample is compatible with the structure of the compound.

Example 11

image5 ON

N H

N image5 SN image5 N

NOO image5

OR

From the piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

4- (3,5-Dimethoxybenzyl) piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained in the form of white solid; LRMS of C20H24N6O4S (M + H) + at m / z = 445. The NMR spectrum

5 obtained from the sample is compatible with the structure of the compound. Example 12

image5 ON

N H

N image5 SN image56

N OR

F

F

From the hydrochloride of (7-methoxy-thiazolo [5.4

10 d] piperazine-1-carboxylic acid pyrimidin-2-yl) -amide and 3- (3-Trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained as a solid White; LRMS of C19H19F3N6O3S (M + H) + at m / z = 469. The

15 NMR spectrum obtained from the sample is compatible with the compound structure

Example 13

image5 ON

N

H

N image5 SN image5 N

NOO image5 FF

From the hydrochloride of (7-methoxy-thiazolo [5.4

d] piperazine-1-carboxylic acid pyrimidin-2-yl) -amide and

5-Difluoromethoxy-benzaldehyde is obtained (7-methoxy-thia

4- (3-Difluoric acid zolo [5,4-d] pyrimidin-2-yl) -amide

methoxy-benzyl) -piperazine-1-carboxylic solid

White; LRMS of C19H20F2N6O3S (M + H) + at m / z = 451. The

NMR spectrum obtained from the sample is compatible with the 10 structure of the compound. Example 14

image57

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 15 3,5-dichloro-benzaldehyde is obtained ((7-methoxy-thiazolo

4- (3,5-Dichloro-ben acid [4,4-d] pyrimidin-2-yl) -amide

cil) -piperazine-1-carboxylic acid in the form of a white solid; EMLR of C18H18Cl2N6O2S (M + H) + at m / z = 454. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 15

image58

From the hydrochloride of (7-methoxy-thiazolo [5.4

d] piperazine-1-carboxylic acid pyrimidin-2-yl) -amide and

3-hydroxy-benzaldehyde is obtained ((7-methoxy-thiazolo [5,4

10 d] 4- (3-Hydroxy-benzyl) piperazine-1-carboxylic acid pyrimidin-2-yl) -amide as a matt white solid; EMLR of C18H20N6O3S (M + H) + at m / z = 401. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

15 Example 16

image59

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 3- (2-Hydroxy-ethoxy) -benzaldehyde is obtained 4- (3- (2-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide

5-hydroxy-ethoxy) -benzyl] -piperazine-1-carboxylic acid in the form of matte white solid; LRMS of C20H24N6O4S (M + H) + at m / z = 445. The NMR spectrum obtained from the sample is compatible with the compound structure

Example 17

image5 ON

N H

N image5 SN image5 image5 N image5

N O Cl

10

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 1- (3-Chloro-thiazolo [5,4-d] pyrimidin-2-yl) -amide acid 4- (1- (3-chloro-phenyl))

Ethyl] -piperazine-1-carboxylic acid as a white solid mate; LRMS of C19H21ClN6O2S (M + H) + at m / z = 433. The spectrum NMR obtained from the sample is compatible with the structure of the compound.

image60

image5

image61

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

5-Phenyl-acetaldehyde trifluoroacetate is obtained from the (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4fenetyl-piperazine-1-carboxylic acid as a white solid mate; LRMS of C19H22N6O2S (M + H) + at m / z = 399. Example 19

image62

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 4- (4-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide acid 4- (4-trifluoromethyl) -benzaldehyde is obtained

15 fluor-3-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid in white solid form; EM-ES-HR m / e calculated for the C19H18F4N6O2S (M + H) + = 471,1221; found = 471.1220.

Example 20

image5 ON

HN

N image5 SN image5 image5 N image5

N OR

N

F F

F

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

5- (6-Trifluoromethyl-pyridin-3-ylmethyl) -piperazine-1- (4-trifluoromethyl-pyridin-3-ylmethyl) -piperazine-1- (5-trifluoromethyl-pyridine-3-carbaldehyde) carboxylic in white solid form; EM-ES-HR m / e calculated for the C18H18F3N7O2S (M + H) + 454.1268; found = 454.1272.

10 Example 21

image63 OR

image5 OR image5

F HON

H FN

F

N image5 SN

OH

N OR

Cl

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 5-Chlorosalicylaldehyde is obtained the trifluoroacetate salt of 15 (4-Chloro-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

of white solid; EM-ES-HR m / e calculated for C18H20N6O3SCl (M + H) + = 435,1001; found = 435,1002. Example 22

image5 ON

HN N image64 SN O

OR image5 OR

OH

5 From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 3-formylphenoxyacetic acid is obtained trifluoroacetate salt of the {3- [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-ylmethyl] -phenoxy} -acetic acid as a solid

10 white; EM-ES-HR m / e calculated for C20H23N6O5S (M + H) + = 459.1445; found = 459.1446. Example 23

image65

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,415 d] pyrimidin-2-yl) -amide hydrochloride and 3,5-dichlorosalicylaldehyde the trifluoroacetate salt is obtained

of the acid (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide 4- (3,5-Dichloro-2-hydroxy-benzyl) -piperazine-1-carboxylic acid in white solid form; EM-ES-HR m / e calculated for the C18H19N6O3SCl2 (M + H) + = 469.0611; found = 469.0613.

Example 24

image66

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 3-fluorsalicylaldehyde is obtained the trifluoroacetate salt of

10 (4-3-Fluoro-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide of white solid; EM-ES-HR m / e calculated for the C18H20N6O3SF (M + H) + = 419,1296; found = 419.1298. Example 25

image67

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

5-Fluorsalicylaldehyde is obtained the trifluoroacetate salt of 4 (5-fluor-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide of white solid; EM-ES-HR m / e calculated for the C18H20N6O3SF

5 (M + H) + = 419,1296; found = 419.1298. Example 26

image68

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

10 3-methyl salicylaldehyde is obtained the trifluoroacetate salt of acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4- (2-Hydroxy-3-methyl-benzyl) -piperazine-1-carboxylic acid in white solid form; EM-ES-HR m / e calculated for the C19H23N6O3S (M + H) + = 415.1547; found = 415.1547.

15 Example 27

image64 ON

H

N image5

SN image5 N OH OO

OH

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and

3-formylsalicylic acid is obtained trifluoroacetate salt of 2-hydroxy-3- [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-carbamoyl) -piperazin-1-ylmethyl] -benzoic acid as a solid White; EM-ES-HR m / e calculated for C19H21N6O5S (M + H) + =

5,445,1289; found = 445.1291. Example 28

image69

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 10 (6-Morpholin-4-yl-pyridin-3-yl-methyl) - (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide piperazine-1-carboxylic form white solid; LRMS of C21H26N6O3S (M + H) + at m / z = 470. The NMR spectrum obtained from the sample is compatible with the

15 structure of the compound.

Example 29

Synthesis of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl)

4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid amide

N

OR image5

OR image5

image70 pyridine

OR image5

image5 N

N image5 image5 N

N

N

N

image5 N +

N

N

HN

NH2

H

S

S

N

image5

A triphosgene mixture (165 mg, 0.55 mmol) and tetrahydrofuran (10 ml) with pyridine (260 mg, 5 3.30 mmol), then 7-methoxythiazol [5,4-d] pyrimidin-2-ylamine (200 mg, 1.10 mmol) is added portionwise. Be keep the mixture under stirring at 25oC for 2 h. The reaction mixture is then treated with 1 - [(2-pyridyl) methyl] piperazine (390 mg, 2.20 mmol). The 10 stirring the mixture at 25 ° C for a further 2 h. Then interrupt the reaction with a slow addition of water. Be Extract the aqueous phase with ethyl acetate. The phase is washed organic with a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and concentrated with 15 empty. By flash chromatography (Merck silica gel 60, 230-400 mesh, 98/2 mixture of methylene chloride / methanol) se obtains (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide from 4-pyridin-2-ylmethyl-piperazine-1-carboxylic acid (43 mg, 10%) in the form of slightly yellow oil; EM-LR of

20 C17H19N7O2S (M + H) + at m / z = 385. The NMR spectrum obtained from the Sample is compatible with the structure of the compound. In a similar way the compounds of the Examples 30-36 as follows:

Example 30

image71

From (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) methylamine and 1-benzylpiperazine, (7-methoxy) is obtained

4-Benzylpiperazine-1-carboxylic acid thiazolo [5,4-d] pyrimidin-2-yl) -amide as a yellow solid; ESHR-m / e calculated for C18H21N6O2S (M + H) + = 385.1441; found = 385,1441. Example 31

image72

From (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) methylamine and 4- (4-fluorophenyl) -2,8-diaza-spiro [4.5] decan-1one is obtained 4- (4-Fluoro-phenyl) -1-oxo-2,8-diazaspiro15 [4,5] decane-8 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide -carboxylic (59 mg, 24%) as a solid White; LRMS of C21H21FN6O3S (M + H) + at m / z = 456. The spectrum

image73

NMR obtained from the sample is compatible with the structure of the compound. Example 32

5 From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 2- (4-trifluoromethyl-phenyl) -morpholine, the 2- (4-Trifluoromethyl-phenyl) -morpholine-4-carboxylic acid (140 mg, 58%) (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide (140 mg, 58%) in white solid form; LRMS of C18H16F3N5O3S (M + H) + at m / z =

10 439. The NMR spectrum obtained from the sample is compatible with The structure of the compound. Example 33

image74

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2

15-ylamine and acid thiazol-2-ylamide hydrochloride piperidine-3-carboxylic acid is obtained 1 - [(7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide] -3-thiazol-2-ylamide

image75

piperidine-1,3-dicarboxylic acid (11 mg, 5.4%) as a solid White; MS-ES-HR m / e calculated for C16H17N7O3S2 (M + Na) + = 442.0726; found = 442.0729.

Example 34

From 3- (4-chlorobenzyl) pyrrolidine oxalate is obtained from 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and oxalate 3 (4-Chloro-benzyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide (21 mg, 9.3%) in

10 white solid form; EM-ES-HR m / e calculated for the C18H18ClN5O2S (M + H) + = 404.0943; found = 404.0944. Example 35

image5 ON

image5 FHN F

N image5 SN

N F

OR

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2

15-ylamine and 3- (4-trifluoromethyl-benzyl) 3- (4- (trifluoromethyl) benzyl] pyrrolidine oxalate is obtained from 3- (4-trifluoromethyl-benzyl) (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide ) -pyrrolidine-1 carboxylic acid (12 mg, 5%) as a white solid; EM-ES-HR m / e calculated for C19H18F3N5O2S (M + H) + = 438.1206; found

20 = 438,1207.

image76

Example 36

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 3- (4-methylphenylsulfonyl) pi hydrochloride

5-Rrolidine (3- (toluene-4-sulfonyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide (78 mg, 32.8%) is obtained in the form of white solid; ESHR-MS m / e calculated for C18H19N5O4S2 (M + H) + = 434.0951; found = 434.0951.

10 Example 37 Synthesis of 4- (4-Chloro-2-methanesulfonyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide.

image5 Cl image77 OR

OO

image5 OR image5

OR image5

OR image5

N image5 N image5 image5 NS

N image5 N image5 image5 NH

Br

N

N

OR

N

OR

N

+

S

S Cl

N HCl N

fifteen A mixture of the piperazine-1-carboxylic acid (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide hydrochloride (obtained in example 1, 625 mg, 1.70 mmol) and N, N-dimethylformamide (5 ml) with N, N-diisopropylethylamine (660 20 mg, 5.10 mmol), then 1- (bromomethyl) -4 is added

Chloro-2- (methylsulfonyl) -benzene (530 mg, 1.87 mmol). Be keep the reaction mixture under stirring at 80 ° C for 3

h. The reaction mixture is then poured onto Water. The aqueous phase is extracted with ethyl acetate. Wash 5 the organic phase with a saturated aqueous chloride solution sodium, dried with magnesium sulfate, filtered and Concentrate with vacuum. By flash chromatography (silica gel Merck 60, 230-400 mesh, 80/20 mixture of hexanes / acetate ethyl) (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) is obtained

10 4- (4-Chloro-2-methanesulfonyl-benzyl) -piperazine-1-carboxylic acid amide (580 mg, 69%) as a white solid mate; LRMS of C19H21ClN6O4S2 (M + H) + at m / z = 496. The spectrum NMR obtained from the sample is compatible with the structure of the compound.

In a similar way the compounds of the Examples 38-42 as follows: Example 38

From the hydrochloride of (7-methoxy-thiazolo [5.4

20 d] piperazine-1-carboxylic acid pyrimidin-2-yl) -amide and 3,4-(3,4-Dichlorobenzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide (64-dichlorobenzyl bromide) (64 mg, 26%) in the form of

image78

image79

white solid; LRMS of C18H18Cl2N6O2S (M + H) + at m / z = 453. The NMR spectrum obtained from the sample is compatible with the compound structure

Example 39

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 4-methoxy-3- (trifluoromethyl) benzyl bromide is obtained the 4- (4-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

10-methoxy-3-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (90 mg, 34%) as a slightly brown solid; EM-LR of C20H21F3N6O3S (M + H) + at m / z = 482. The NMR spectrum obtained from The sample is compatible with the structure of the compound. Example 40

image80

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 5-Bromomethyl-2-methoxy-benzonitrile gives (7-methoxy

4- (3-Cyano-4-methoxy-benzyl) -piperazine-1-carboxylic acid thiazolo [5,4-d] pyrimidin-2-yl) -amide (25 mg, 6%) as of slightly brown solid; EM-LR of C20H21N7O3S (M + H) + a m / z = 439. The NMR spectrum obtained from the sample is

5 compatible with the structure of the compound. Example 41

image81

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 4- (3,5-Bis-trifluoromethyl-benzyl) -piperazine- (4- (3,5-bis-trifluoromethyl-benzyl) -piperazine- (4- (3,5-bis-trifluoromethyl-benzyl) -piperazine-) 1-carboxylic (130 mg, 28%) in the form of a matt white solid; EM-LR of C20H18F6N6O2S (M + H) + at m / z = 520. The NMR spectrum obtained from the sample is 15 compatible with the structure of the compound.

Example 42

image82

(e) From (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide hydrochloride of piperazine-1-carboxylic acid and 1- (2-bromoethoxy) -3- (trifluoromethyl) - benzene obtains (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide from

5 4- [2- (3-Trifluoromethyl-phenoxy) -ethyl] -piperazine-1-carboxylic acid (39 mg, 9%) as a brown solid; EM-LR of C20H21F3N6O3S (M + H) + at m / z = 482. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

Example 43

Synthesis of 4- (4-fluor-3-trifluoromethyl-benzoyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide

image83

F

A solution of 25 ° C is stirred overnight.

Piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide hydrochloride (obtained in the example 1, 300 mg, 0.91 mmol), 4-fluor-3- (trifluoromethyl) benzyl chloride (140 ml, 0.92 mmol) and triethylamine (3.4

ml, 2.27 mmol) in methylene chloride (15 ml). The reaction mixture is then poured into water and extracted with ethyl acetate. Organic phases meet, wash with a saturated aqueous solution of sodium bicarbonate, 5 dry with sodium sulfate, filter and concentrate with empty. The resulting solids are recrystallized twice in a 2: 1: 1 mixture of methanol / dimethyl sulfoxide / dioxane, obtaining (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide of 4- (4-fluor-3-trifluoromethyl-benzoyl) -piperazine-1 acid

Carboxylic (134 mg, 30.5%) in the form of white solid; ESHR-m / e calculated for C19H16F4N6O3S (M + H) + = 485,1014; found = 485.1014.

In a similar way the compounds of the Examples 44-46 as follows: 15 Example 44

image5 ON

H

N

image5 OR

N image5

SN image5 image5 N

N

OR

N

F

F

F

From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 6-trifluoromethyl-nicotinoyl chloride is obtained the (7

4- (6-Trifluoromethyl-pyridine-3-carbonyl) -piperazine-1-carboxylic acid methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

in the form of white solid; EM-ES-HR m / e calculated for the C18H16F3N7O3S (M + H) + = 468,1060; found = 468.1058.

Example 45

image84

5 From piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide hydrochloride and 3- (3-Chloro-benzoyl) piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained as a white solid ; EM-LR of

10 C18H17ClN6O3S (M + H) + at m / z = 433. The NMR spectrum obtained from The sample is compatible with the structure of the compound. Example 46

image5 ON

N H

image5 OR

N image5 OS NNSN OR

Cl

From the hydrochloride of (7-methoxy-thiazolo [5.4

15 d] piperazine-1-carboxylic acid pyrimidin-2-yl) -amide and 3- (3-Chlorobenzenesulfonyl) -piperazine-1-carboxylic acid (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained as a solid

matte white; LRMS of C17H17ClN6O4S2 (M + H) + at m / z = 469. The NMR spectrum obtained from the sample is compatible with the compound structure

Example 47

Synthesis of 4- [3- (trifluoromethyl) phenyl] piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide

OR image5 HN image5 image5 N image5 N image5 image5 N image5 Cl

FF FF

F F

Step 1: a triphosgene mixture is slowly treated

10 (3.2 g, 10.85 mmol) and tetrahydrofuran (10 ml) with pyridine (1.72 g, 21.72 mmol), added with a syringe. The resulting white suspension is then treated with 1 [3- (trifluoromethyl) phenyl] piperazine (500 mg, 2.17 mmol) added in portions. The reaction mixture is maintained in

Stirring at 25 ° C for 18 h. It is then interrupted Slowly the reaction by adding water. The phase is extracted aqueous with methylene chloride. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and concentrated in vacuo,

20 obtaining 4- (3-trifluoromethyl-phenyl) -piperazine-1-carbonyl chloride (500 mg, 79%). The NMR spectrum obtained from The sample is compatible with the structure of the compound.

OR image5 image5 OR

OR image5

OR image5

image5 N

N image5 image5 N

N

N

N image5 image5 N

N

NH2

+

N

Cl

image5 F

H

S

image5 FN

S

N

F

FF

F

Step 2: a nitrogen atmosphere is treated at 25 ° C mixture of 7-methoxy-thiazol [5,4-d] pyrimidin-2-ylamine (100 mg, 5 0.55 mmol) and tetrahydrofuran (10 ml) with sodium hydride (60% suspension in mineral oil, 30 mg, 0.66 mmol). The reaction mixture is stirred at 50 ° C for 30 min. TO The reaction mixture is then treated with N, N-diisopropylethylamine (215 mg, 1.65 mmol) and 4- [310 (trifluoromethyl) phenyl] piperazine-1-carbonyl chloride (180 mg, 0.60 mmoles). This mixture is stirred at 50 ° C for 3 d. Later concentrate the reaction mixture under vacuum, pour over water and extracted with ethyl acetate. The phase is washed organic with a 2N aqueous solution of hydrochloric acid and A saturated aqueous solution of sodium chloride is dried with magnesium sulfate, filtered and concentrated in vacuo. By flash chromatography (Merck silica gel 60, 230-400 mesh, 80/20 mixture of hexanes / ethyl acetate) 4- (3-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained

20 (trifluoromethyl) phenyl] piperazine-1-carboxylic acid (70 mg, 29%) in slightly brown solid form; EM-LR of the C18H17F3N6O2S (M + H) + at m / z = 438. The NMR spectrum obtained from the sample is compatible with the structure of the compound. In a similar way the compounds of the

25 examples 48-58 as follows:

Example 48

image85

From 7-methoxy-thiazol [5,4-d] pyrimidin-2-ylamine and 5-chloro-1,2-dihydro-1- (methyl hydrochloride)

5 sulfonyl) spiro [3H-indole-3,4'-piperidine] 5-chloro-1,2-dihydro-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) -1 (methylsulfonyl) ) spiro [3H-indole-3,4'-piperidine] -1'-carboxamide (214 mg, 77%) as a slightly brown solid; LRMS of C20H21ClN6O4S2 (M + H) + at m / z = 508. The NMR spectrum

10 obtained from the sample is compatible with the structure of the compound. Example 49

image86

F

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl

15 amine and 4- (6-fluor-2-oxo-benzooxazol-3-yl) piperidine-1-carbonyl chloride gives (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide of 4- (6-fluor-2-oxo-benzooxazol-3-yl) -piperidine-1-carboxylic acid (184 mg, 75%) as

of slightly brown solid; LRMS of C19H17FN6O4S (M + H) + a m / z = 444. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 50

image87

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 5-methoxy-1,2-dihydro-1-methylpyrro- [3H-indole3,4'-piperidine] 1 , 2-dihydro-5-methoxy-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) -1-methylstyrene [3H-indole

10,4’-piperidine] -1’-carboxamide in the form of a yellow solid; LRMS of C21H24N6O3S (M + H) + at m / z = 440. The NMR spectrum obtained from the sample is compatible with the structure of the compound. Example 51

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 1- (cyclopropylmethyl) -1,2-dihydro-spiro [3H-indole-3,4'-piperidine] hydrochloride, the one

image88

(cyclopropylmethyl) -1,2-dihydro-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) spiro [3H-indole-3,4'-piperidine] -1'-carboxamide in yellow solid form; LRMS of C23H26N6O2S (M + H) + at m / z =

450. The NMR spectrum obtained from the sample is compatible with

5 the structure of the compound. Example 52

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 5-chloro-1- (cyclopropylmethyl) hydrochloride

10 1,2-dihydro-spiro [3H-indole-3,4'-piperidine] gives 1 (cyclopropylmethyl) -1,2-dihydro-5-chloro-N- (7-methoxythiazole [5,4d] pyrimidin -2-yl) spiro [3H-indole-3,4'-piperidine] -1'-carboxamide as a yellow solid; EM-LR of C23H25ClN6O2S (M + H) + at m / z = 484. The NMR spectrum obtained from the sample is

15 compatible with the structure of the compound. Example 53

image89

image90

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 5-methyl-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, the 4- (5-Methyl-2-oxo-2,3-dihydro-benzo) (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

Imidazol-1-yl) -piperidine-1-carboxylic acid solid slightly yellow; LRMS of C20H21N7O3S (M + H) + at m / z = 439. The NMR spectrum obtained from the sample is compatible with the compound structure Example 54

image91

From ethyl 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and ethyl 3- (4-trifluoromethoxy-benzyl) -piperidine-3-carboxylate, 1- (7-methoxy- thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -3- (4-trifluoromethoxy-benzyl) -piperidine

Ethyl 3-carboxylate as a yellow solid; EM-LR of C23H24F3N5O5S (M + H) + at m / z = 539. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

Example 55

image92

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl

amine and 4- (4-fluorophenyl) -2,8-diaza-spiro [4.5] decan-1

5a (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) is obtained

4- (4-fluorophenyl) -1-oxo-2,8-diaza-spiro acid amide

[4.5] decane-8-carboxylic solid slightly

Brown; LRMS of C21H21FN6O3S (M + H) + at m / z = 456. The spectrum

NMR obtained from the sample is compatible with the structure 10 of the compound. Example 56

From 7-methoxy-thiazol [5,4-d] pyrimidin-2-ylamine and 4'-hydroxy-3 ', 4', 5 ', 6'-tetrahydro-2'H15 [2, 4'] bipyridinyl-1'-carbonyl gives 4'-hydroxy3 ', 4', 5 ', 6'- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide tetrahydro-2H- [2,4 '] bipyridinyl-1'-carboxylic acid in matte white solid form; LRMS of C17H18N6O3S (M + H) + at m / z

image93

image94

= 386. The NMR spectrum obtained from the sample is compatible with the structure of the compound. Example 57

5 From 7-methoxy-thiazol [5,4-d] pyrimidin-2-ylamine and 4- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carbonyl chloride obtains 4- (2-oxo-2,3-dihydrobenzoimidazol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide; EM-ES-HR m / e

10 calculated for C18H20N7O3S (M + H) + = 426.1343; found =

426.1344. Example 58 Acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

3,4-Dihydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1-carbo15 xyl

image95

F

Stir at room temperature overnight. mixture of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

4- (3-Trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid (from example 67) (100 mg, 0.23 mmol), N-methylmorpholine N-oxide (60 mg, 0 , 51 mmol) and osmium tetroxide (4% by weight in water, 13 µl, 0.053 mmol) in acetone (9.5 ml) and water (1 ml). The reaction is stopped with sodium hydrogen sulfate and stirred at room temperature for 10 minutes. The mixture is filtered and the filtered liquid is diluted with methanol and absorbed on silica gel. Column chromatography (6 • 10% methanol in 10 methylene chloride) gives 3,4-dihydroxy-4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide ( 3-Trifluoromethyl-phenyl) piperidine-1-carboxylic acid (25 mg, yield: 23%) as a slightly brown powder; LRMS of C19H18F3N5O4S (M + H) + at m / z = 470. The NMR spectrum obtained from the sample is compa

15 possible with the structure of the compound. Example 59 Synthesis of (7-methoxy-thiazolo trifluoroacetate)

4- (3,4-Dihydro-1 Hisoquinolin-2-yl) -piperidine-1-carboxylic acid [5,4-d] pyrimidin-2-yl) -amide

OR

twenty Step 1: a triphosgene solution is treated at 0 ° C (2.84 g, 9.6 mmol) in methylene chloride (100 ml) with a solution of 1-benzyl-piperidin-4-one (6.0 g, 31.7 mmol) in methylene chloride (100 ml). The mixture is allowed to warm 25 reactant at 25oC and stir at 25oC overnight. TO The mixture is then concentrated in vacuo. By chromate-

image96

Flash spelling (Merck silica gel 60, 230-400 mesh, gradient elution: 60/40 ethyl acetate / hexanes) se obtains 4-oxo-piperidine-1-carbonyl chloride (3.9 g, 76%) in the form of brown oil. The NMR spectrum obtained from

5 the sample is compatible with the structure of the compound.

image5 OR image5 OR

image5 OR

NN HN NNH2 Cl NN image5

+

S

SN image5 ON

NO OR

Step 2: a solution of 7-methoxythiazolo [5,4-d] pyrimidin-2-ylamine (2.2 g, 12.1 mmol) is treated at 25 ° C tetrahydrofuran (70 ml) with sodium hydride (60% in

10 mineral oil, 1.45 g, 36 mmol). A slight gas evolution is observed. The purple suspension is heated resulting at 70oC for 1 h. Then the reaction mixture at 25 ° C and treated with N, N-diisopropylethylamine (6.5 ml, 37.4 mmol) and a chloride solution

15 of 4-oxo-piperidine-1-carbonyl (3.9 g, 24.2 mmol) in tetrahydrofuran (10 ml). The reaction mixture is stirred at 70oC overnight. The mixture is then concentrated Reactant under vacuum, dissolved in methanol and absorbed on silica gel (6 g). The silica gel is divided into two

20 equal lots. By ISCO chromatography (120 g, silica gel, gradient elution: 5/95 methanol / methylene chloride) se obtains a dark brown, impure solid (1.09 g). Trituration of the solid in ethyl acetate gives 4-oxo (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

25 piperidine-1-carboxylic acid (0.88 g, 24%) as a solid

slightly brown; LRMS of C12H13N5O3S (M + H) + at m / z = 308. The NMR spectrum obtained from the sample is compatible with the compound structure

image5 OR

image5 OR

N HN NN image5 HN N image5 SN image5 ON S NNN

O o

5 Step 3: A solution of the 4-oxo-piperidine-1-carboxylic acid (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide (50 mg, 0.16 mmol) is treated at 25 ° C ) in methanol (5 ml) with 1,2,3,4-tetrahydro-isoquinoline (22 mg, 0.16 mmol), acid acetic acid (28 ml, 0.49 mmol) and sodium cyanoborhydride (30 mg,

10 0.48 mmol). The reaction mixture is stirred at 25 ° C for one night. The reaction mixture is then concentrated. with emptiness By high performance liquid chromatography (gradient of 10% acetonitrile in water with 0.1% of 90% trifluoroacetic acid in water with 0.1% acid

Trifluoroacetic) trifluoroacetate is obtained from 4- (3,4-dihydro-1H-isoquinolin-2-yl) -piperidine-1- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide carboxylic (18 mg, 21%) in the form of white solid; EM-LR of C21H24N6O2S (M + H) + a m / z = 425. The NMR spectrum obtained from the sample is compa

20 possible with the structure of the compound. In a similar way the compounds of the Examples 60-64 as follows:

Example 60

image5 OR

F

image5 OR image5 HO

F

N FN H

N image5 SN image63

N OR

From 4-oxo-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide and 2.35 dihydro-1H-isoindole, trifluoroacetate is obtained from 4- (1,3-dihydro-isoindol-2-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide slightly brown solid; LRMS of C20H22N6O2S (M + H) + at m / z =

411 10 Example 61

image63 OF

image5 O HO FN

F

N H

N image5 SN

N OR

From the (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide of 4-oxo-piperidine-1-carboxylic acid and 3-phenyl-pyrrolidine, the trifluoroacetate of the (7

4- (3-Phenyl-pyrrolidin-1-yl) -piperidine-1-carboxylic acid methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide slightly brown solid; LRMS of C22H26N6O2S (M + H) + at m / z =

439

Example 62

image5 OF

image5 OR image5 HO F

N image5 HF N image5

SN N

NO

image26

From the (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide of 4-oxo-piperidine-1-carboxylic acid and of the phenyl-pyrrolidine the trifluoroacetate of the (7-methoxy) is obtained 4- (2-phenyl-pyrrolidin-1-yl) -piperidine-1-carboxylic acid thiazolo [5,4-d] pyrimidin-2-yl) -amide slightly brown solid; LRMS of C22H26N6O2S (M + H) + at m / z =

439 10 Example 63

image5 OF image5 OR image5 HO

N image5 image5 FN HF

N SN

NO

image26

From the (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide of 4-oxo-piperidine-1-carboxylic acid and 2,3-dihydro-1H-indole, the trifluoroacetate of the 4- (2,3-dihydro-indol-1-yl) -piperidine-1-carboxylic acid (715-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

slightly brown solid; LRMS of C20H22N6O2S (M + H) + at m / z =

411 Example 64

image5 OR image5 Or FN

NH HON image5 FFS N image5 N image5 NO

Cl

5 From 4-oxo-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide and 5-chloro2,3-dihydro-1H-indole obtains 4- (5-chloro-2,3-dihydro-indole-1-yl) -piperidine-1-carboxylic acid trifluoroacetate of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

10 slightly brown powder form; EM-LR of C20H21N6O2S (M + H) +

a m / z = 445. Example 65 Synthesis of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl)

4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperi15 dina-1-carboxylic acid amide

image5 OH image5 OH

ON

HN Cl

CF3 CF3

Step 1: A triphosgene solution is treated (3.26 g, 0.011 mol) in anhydrous tetrahydrofuran (1000 ml) cooled to -20oC with pyridine (4.45 ml, 0.055 mol). It's about slow

20 the resulting cloudy suspension with a solution of 4

(3-Trifluoromethyl-phenyl) -piperidin-4-ol (9 g, 0.036 mol) in anhydrous tetrahydrofuran (45 ml), maintaining the temperature internal between -20oC and -30oC. The resulting mixture is transferred to an ice bath, which is allowed to warm to 25 ° C for 5 one night, obtaining a slightly brown solution with A small amount of brown precipitate. The reaction mixture under vacuum, obtaining a brown solid. By flash chromatography (Merck silica gel 60, 230-400 mesh, 75/25 hexanes / ethyl acetate) chloride is obtained

10 of 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1-carbonyl (6.89 g, 61%) in the form of transparent and viscous oil. He NMR spectrum obtained from the sample is compatible with the compound structure

image5 OH

image5 OR image5 ON

N

O N H

+ N

N

NH2

N image97

SCl

N NS CF3 O

F3C

Step 2: A mixture of 7-methoxythiazolo [5,4-d] pyrimidin-2-ylamine (2.72 g, 0.015 mol) is treated at 25 ° C tetrahydrofuran (250 ml) with sodium hydride (60% in mineral oil, 1.79 g, 0.045 mol). The suspension is heated at 50 ° C for 1 h and then cooled 0 ° C in a bath

20 ice The reaction mixture cooled with N, Ndiisopropylethylamine (7.8 ml, 0.045 mol) and a solution of 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1carbonyl chloride (6.5 g, 0.021 mol) in tetrahydrofuran (50 ml). The reaction mixture is allowed to warm to 25 ° C for one

night. The mixture is then concentrated in vacuo, obtaining a brown solid, which is collected in acetate ethyl (600 ml). The organic phase is washed with a solution 1N aqueous hydrochloric acid (2 x 200 ml), water (1 x 200 5 ml) and a saturated aqueous solution of sodium chloride (1 x 200 ml), dried over magnesium sulfate, filtered and concentrated with emptiness By ISCO chromatography (330 g, silica gel, gradient elution 8/92 methanol / methylene chloride) is gets a slightly brown solid (3.81 g). It is crushed and 10 solid twice in methylene chloride, obtaining 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide. carboxylic (3.32 g, 49%) as a white solid; EM-LR of the C19H18F3N5O3S (M + H) + at m / z = 454. The NMR spectrum obtained from the sample is

15 compatible with the structure of the compound. In a similar way the compounds of the Examples 66-78 as follows: Example 66

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (3-trifluoromethyl-phenyl) -piperidine-1-carbonyl chloride, (7-methoxy-thiazolo [5] , 4- (3-Trifluoromethyl-phenyl), 4-d] pyrimidin-2-yl) -amide

image98

piperidine-1-carboxylic in the form of a matt white solid; EMLR of C19H18F3N5O2S (M + H) + at m / z = 438. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 67

image99

F

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (3-trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridine-1-carbonyl chloride, the ( 7-methoxy

4- (3-Trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid thiazolo [5,4-d] pyrimidin-2-yl) -amide of slightly brown solid; EM-LR of C19H16F3N5O2S (M + H) + a m / z = 436. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

15 Example 68

image5 ON

N H

N image5 image5 FSNN F

O F

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 3- (3-trifluoromethyl-benzyl) -piperidine chloride

1-Carbonyl is obtained ((7-methoxy-thiazolo [5,4-d] pyrimidin

3- (3-Trifluoromethyl-benzyl) -piperidine-1-carboxylic acid 2-yl) -amide as a slightly brown solid; EM-LR of C20H20F3N5O2S (M + H) + at m / z = 452. The NMR spectrum obtained of the sample is compatible with the structure of the compound.

5 Example 69

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 3-benzyl-pyrrolidine-1-carbonyl chloride, obtains (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide from

10-benzyl-pyrrolidine-1-carboxylic acid as a solid matte white; LRMS of C18H19N5O2S (M + H) + at m / z = 370. The NMR spectrum obtained from the sample is compatible with the compound structure Example 70

image100

image101

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (3-trifluoromethyl-benzenesulfonyl) piperidine-1-carbonyl chloride, (7-methoxy-thiazolo [5,4d] ] 4- (3-Trifluoromethyl-benzene acid) pyrimidin-2-yl) -amide

sulfonyl) -piperidine-1-carboxylic acid in the form of a brown solid; LRMS of C19H18F3N5O4S2 (M + H) + at m / z = 502. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 71

image102

OR

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl chloride is obtained the (7-methoxy-thiazolo [5.4

10 d] 4-Oxo-1-phenyl-1,3,8-triazaspiro [4.5] decane-8-carboxylic acid pyrimidin-2-yl) -amide as a slightly brown solid; LRMS of C20H21N7O3S (M + H) + at m / z = 440. The NMR spectrum obtained from the sample is compatible with the compound structure

15 Example 72

image5 ON

N H

OR

N image5 SN image5 S image5 Cl

N OR

OR

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (4-chloro-benzenesulfonyl) -piperidine-1-carbonyl chloride, (7-methoxy-thiazolo [5, 4-d] pi

4- (4-Chloro-benzenesulfonyl) piperidine-1-carboxylic acid rimidin-2-yl) -amide as a white solid; EM-LR of C18H18ClN5O4S2 (M + H) + at m / z = 468. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

5 Example 73

image5 ON

N H

OR

N image5 SN image5 S image5

N OR

OR

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (toluene-4-sulfonyl) -piperidine-1-carbonyl chloride, (7-methoxy-thiazolo [5, 4-d] pyrimidin-2

10-yl) -amide of 4- (toluene-4-sulfonyl) -piperidine-1-carboxylic acid as a white solid; EM-LR of the C19H21N5O4S2 (M + H) + at m / z = 448. The NMR spectrum obtained from the sample is compatible with the structure of the compound. Example 74

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (3-chloro-phenoxy) -piperidine-1-carbonyl chloride, (7-methoxy-thiazolo [ 4- (3-Chloro-phenoxy) -piperidine-1-carboxylic acid 5,4-d] pyrimidin-2-yl) amide

20 in the form of a matt white solid; LRMS of C18H18ClN5O3S (M + H) +

image103

a m / z = 420. The NMR spectrum obtained from the sample is compatible with the structure of the compound. Example 75

5 (k) From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (4-fluor-benzyl) -piperidine-1-carbonyl chloride, (7-methoxy-thiazolo [ 4- (4-Fluoro-benzyl) -piperidine-1-carboxylic acid 5,4-d] pyrimidin-2-yl) -amide as a slightly brown solid; EM-LR of

10 C19H20FN5O2S (M + H) + at m / z = 402. The NMR spectrum obtained from the Sample is compatible with the structure of the compound. Example 76

image104

image105

From 7-methoxy-thiazolo [5,4-d] pyrimidin-215 ylamine and 2- (1-chlorocarbonyl-piperidine-4-sulfonyl)

methyl benzoate is obtained 2- [1- (7-methoxy-thiazolo [5.4

d] pyrimidin-2-ylcarbamoyl) -piperidine-4-sulfonyl] -benzoate methyl in the form of a slightly brown solid; EM-LR of C20H21N5O6S2 (M + H) + at m / z = 492. The NMR spectrum obtained from the Sample is compatible with the structure of the compound.

Example 77

image106

From 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine and 4- (3-trifluoromethyl-benzyl) -piperidine-1-carbonyl chloride, (7-methoxy-thiazolo [5, 4-d] pi

4- (3-Trifluoromethyl-benzyl) piperidine-1-carboxylic acid rimidin-2-yl) -amide as a slightly solid Brown; LRMS of C20H20F3N5O2S (M + H) + at m / z = 452. The spectrum NMR obtained from the sample is compatible with the structure of the compound.

15 Example 78 Synthesis of 4- (3-Chloro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide

image5 OR image5 image5 image5 image5 OR image5 N

N

H N HN NN image5 image5 OH

S NO SNN N

O o

Cl

A solution of the 4-oxo-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide (obtained in example 59, 100 mg, 0.33 mmol) is treated.

5 in tetrahydrofuran (35 ml), cooled to 0 ° C, with bromide of 3-chlorophenyl magnesium (0.5 M in tetrahydrofuran, 1.6 ml, 0.8 mmoles). The resulting mixture is stirred at 25 ° C for 3 h. TO The reaction mixture is then cooled to 0 ° C and treat with an additional amount of 3-chlorophenyl bromide

10 mg (0.5 M in tetrahydrofuran, 6 ml, 3.0 mmol). Be Let the reaction mixture warm to 25oC and keep at stirring at 25oC overnight. The reaction is then interrupted with methanol and absorbed on gel. silica (6 g). By ISCO chromatography (120 g, silica gel,

15 gradient elution 7/93 methanol / methylene chloride) is obtains (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide from 4- (3-Chloro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid (61 mg, 44%) as a slightly brown solid; EM-LR of C18H18ClN5O3S (M + H) + at m / z = 420. The NMR spectrum obtained from

20 the sample is compatible with the structure of the compound. In a similar way the compound of the example is obtained 79 as follows:

Example 79

image5 ON

N

H

N image5

image5 OH

SN

N

OR

image5 OR

From 4-oxo-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide and bromide 5-4-Hydroxy-4- (3-methoxyphenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 5 in the form of a slightly brown solid; LRMS of C19H21N5O4S (M + H) + at m / z = 416. The NMR spectrum obtained from the sample is compatible with the

10 structure of the compound. Example 80 Synthesis of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl)

4’-hydroxy-6-trifluoromethyl-3 ’, 4’, 5 ’, 6’-tetrahydro-2’H- [2,4’] bipyridinyl-1’-carboxylic acid amide

image5 OR image5 image5 OH

OR image5

N

N image5 OR

image5 F

OR

+

image5 OR

Br n

N

F

F

F

F

F

fifteen Step 1: in a nitrogen atmosphere a mixture is treated of 2-bromo-6- (trifluoromethyl) pyridine (300 mg, 1.33 mmol) in tetrahydrofuran (10 ml) cooled to -78 with n-butyl

lithium (2M solution in tetrahydrofuran, 0.83 ml, 1.33 mmoles). The mixture is stirred at -78 ° C for 15 min. The reaction mixture is then treated with 1-boc-4piperidone (265 mg, 1.33 mmol). The mixture is allowed to warm 5 at 25 ° C and stir at 25 ° C for 1 h. Then the reaction mixture on water. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with a solution aqueous saturated with sodium chloride, dried with sulfate magnesium, filtered and concentrated in vacuo, obtaining

10 4'-hydroxy-6-trifluoromethyl-3 ', 4', 5 ', 6'-tetrahydro-2'H [2,4'] bipyridinyl-1'-carboxylate tert-butyl (450 mg, 98% ) in the form of yellow oil; LRMS of C16H21F3N2O3 (M + H) + a m / z = 346. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

image5 OR image5 image5 OH image5 OH N HN

Or NN

F F

F FF F

fifteen

Step 2: A mixture of 4'-hydroxy-6trifluoromethyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,4'] bipyridinyl1'-carboxylate tert-butyl (450 mg) is treated , 1.30 mmol) and chloride of methylene (5 ml) with trifluoroacetic acid (5 ml). It shakes

20 the reaction mixture at 25 ° C for 30 min. Then The reaction mixture is concentrated under vacuum, obtaining a yellow oil The oil is dissolved in chloride methylene, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride

dico, dried with magnesium sulfate, filtered and concentrated with vacuum, obtaining 6-trifluoromethyl-2 ’, 3’, 5 ’, 6’tetrahydro-1’H- [2,4’] bipyridinyl-4’-ol (320 mg, 100%) in yellow oil form; LRMS of C11H13F3N2O3 (M + H) + at m / z =

5 246. The NMR spectrum obtained from the sample is compatible with The structure of the compound.

image5 OH image5 image5 image5 image5 OR

OR image5 image5 OH

HN

N image5 N

N

OR

OR

N

N

+

H

N

NO

S

N

N

N

F

F

H f

F

S

N

F

F

Step 3: a mixture of 6-trifluoromethyl2 ’, 3’, 5 ’, 6’-tetrahydro-1’H- [2,4’] bipyridinyl-4’-ol (320 mg, 10 1.30 mmol) and acetonitrile (15 ml) with (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -phenyl carbamate (360 mg, 1.18 mmol). The mixture is stirred at reflux for 2 h. Then the reaction mixture was poured into a solution saturated aqueous sodium bicarbonate. The phase is extracted 15 aqueous with methylene chloride. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and concentrated in vacuo. By flash chromatography (Merck silica gel 60, 230-400 mesh, 98/2 methylene chloride / methanol) (7-methoxy)

4'-Hydroxy-6-trifluoromethyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [2,4'] thiazolo [5,4-d] pyrimidin-2-yl) -amide bipyridinyl1'-carboxylic acid (94 mg, 17%) as a white solid; EM-LR of C18H17F3N6O3S (M + H) + at m / z = 454. The NMR spectrum obtained of the sample is compatible with the structure of the compound.

Example 81

Synthesis of 4-acetylamino-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide

image107

A solution of the 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide solution is treated by dripping example 65, 100 mg, 0.22 mmol) in acetonitrile (0.16 ml) and

10 glacial acetic acid (0.21 ml), cooled to 0 ° C, with acid concentrated sulfuric acid (0.21 ml). The mixture is allowed to warm resulting at 25 ° C. After stirring for 2 h, the reaction mixture with water, neutralized with a solution saturated with sodium bicarbonate and extracted with acetate

15 ethyl. The extracts are dried with sodium sulfate, filtered and concentrate under vacuum. By liquid chromatography of high efficiency (gradient of acetonitrile in water with 0.1% trifluoroacetic acid) and subsequent lyophilization of the desired fractions gives (7-methoxy-thiazolo [5,4-d] piri

4-acetylamino-4- (3-trifluoromethylphenyl) -piperidine-1-carboxylic acid (37 mg, 28%) as a mid-2-yl) -amide white powder; EM-ES-HR m / e calculated for C21H22N6O3SF3 (M + H) + = 495.1421; found = 495.1424.

Example 82

Synthesis of the 4-amino-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide hydrochloride

image5 OR

image5 OR

N

H

N

N

H

N image5

H

image5 OH N

N image5 image5 Cl

N

SNN

SN

N

OR

OR

OR

CF3

CF3

5 Step 1: a mixture of 4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is treated carboxylic (obtained in the manner described in example 65, 114 mg, 0.25 mmol) and acid 10 acetic acid (0.24 ml) with chloroacetonitrile (0.20 ml, 3.10 mmoles). The reaction mixture is subjected to ultrasound in a water bath until all of the solid dissolves and then it cools to 0oC. The reaction mixture is treated at 0 ° C with concentrated sulfuric acid (0.24 ml). One time After the addition is finished, the reaction mixture is heated to 25 ° C and stir at 25 ° C for 2 h. Then the Mix with water and extract with ethyl acetate. Wash the organic phase with a saturated aqueous bicarbonate solution sodium and a saturated aqueous solution of sodium chloride, it Dry with sodium sulfate, filter and concentrate in vacuo. The resulting material is triturated with diethyl ether, obtaining (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4- (2-Chloro-acetylamino) -4- (3-trifluoromethyl-phenyl) -pipe acid

ridine-1-carboxylic (88 mg, 67%) in the form of white solid mate. This material is used without further purification.

OR image5 OR

image5 N image5 image108 N image5 HN H HCl N image5 NN image5 image5 NH2 HCl S NN S NOO O

CF3 CF3

Step 2: in a sealed tube it is heated at 80 ° C for

5-18 h a mixture of 4- (2-chloro-acetylamino) -4- (3-trifluoromethyl-phenyl) -piperidine- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 1-carboxylic (81 mg, 0.15 mmol) and thiourea (15.4 mg, 0.20 mmol) in ethanol / acetic acid (0.5 ml of a 5: 1 mixture of ethanol / acetic acid). Then

The mixture is allowed to cool to 25 ° C, diluted with water (5 ml) and It leaks. The filtered liquid is neutralized with a solution 1N aqueous sodium hydroxide and then extracted with acetate of ethyl. The organic phase is washed with an aqueous solution. saturated with sodium chloride, dried with sodium sulfate, dried

15 filtered and concentrated in vacuo, obtaining 35 mg of crude material. This material is dissolved in methanol / chloride of methylene and punctured in 2 silica gel plates of preparative thin layer chromatography (thickness: 0.5 mm), which elute with 10% methanol in methylene chloride, obtain

20 denying a white powder (26 mg). This material dissolves in dioxane and treated with a 4N solution of hydrochloric acid in dioxane (1 ml). The resulting solution is concentrated and lyophilized, obtaining the 4-amino acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide hydrochloride salt.

4- (3-Trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (27 mg, 37%) as a slightly yellow solid; EM-ES-HR m / e calculated for C19H20N6O2SF3 (M + H) + 453.1315; found = 453.

Example 83

Synthesis of 4- (4-fluor-3-trifluoromethyl-benzylamino) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide

image5 OR image5 OR

N NHN HNN image5 N image5 HSON SN image5 N image5 NOOO

OR

Step 1: a solution is heated at reflux for 1 h

10 of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -carbamate of phenyl (6 g, 19.8 mmol) and tertbutyl piperidin-4-yl-carbamate (4.37 g, 21.8 mmol) in acetonitrile (400 ml) and then it is stirred at 25 ° C overnight. The solid resulting by filtration, rinsed with acetonitrile

15 and dried under vacuum, obtaining [1- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperidin-4-yl] -carbamate of tert-butyl (7.3 g, 90%) as a white solid; EM-ES-HR m / e calculated for C17H24N6O4S (M + H) + 409.1653; found = 409,1653.

image5 OR

image5 OR

N HN CF3COOH NN image5 HNH N image5 SN image5 N image5 NSN image5 NH2O

O N OO

twenty

Step 2: A mixture of [1 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperidin-4-yl] -tert-butyl carbamate (14.5 g) is stirred at 25 ° C ) and trifluoroacetic acid (100 ml). The reaction mixture is concentrated in vacuo. Be

5 crush the resulting residue with ether and dry under vacuum, obtaining the 4-aminopiperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide salt (14.4 g, 100%) as a solid White.

image5 OR

image5 OR

CF3COOH

N

H

N

N

H

N

N image5

N image5

image5 CF3

H

S

N image5 NH2

N

S

N image5 N image5

N

OR

OR

10 Step 3: a suspension of the acid salt is treated 4-Amino-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide trifluoroacetic acid (1.82 g, 4.30 mmol) in methanol with N, N-diisopropylethylamine (1.5 ml, 15 6.50 mmol), 4-fluor-3- (trifluoromethyl) benzaldehyde (1.3 ml, 6.50 mmol) and toluene. The resulting mixture is stirred at 25 ° C. for 1 h and concentrated in vacuo. This is repeated procedure until the reaction mixture is homogeneous, then it dissolves in toluene. A concentration is made 20 final to remove toluene, the mixture is diluted reactant with dichloroethane (100 ml) and treated with acid acetic acid (0.26 g) and sodium triacetoxyborohydride (2.73 g, 13 mmoles). The resulting reaction mixture is maintained in stirring at 25oC overnight. Then poured 25 the reaction mixture on water and extracted with acetate

ethyl. The organic phase is washed with an aqueous solution. saturated with sodium bicarbonate, dried with sodium sulfate, Filter and concentrate under vacuum. By flash chromatography (Merck silica gel 60, 230-400 mesh, elution of 5 gradient 1: 1 ethyl acetate / hexanes) an oil is obtained colorless. This oil is dissolved in diethyl ether and concentrated under vacuum, obtaining 4- (4-fluor-3-trifluoromethylbenzylamino) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide (530 mg, 25% ) fit

10 white foamed solid; EM-ES-HR m / e calculated for the C20H20F4N6O2S (M + H) + = 485.1378; found = 485.1378. In a similar way the compound of the example is obtained 84 as follows: Example 84

image5 ON

H

N

N image5

H

image5 F

S NN

N

F

OR

N

F

fifteen From the salt of the trifluoroacetic acid of the (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide of 4-aminopiperidine-1-carboxylic acid and 6-trifluoromethyl-pyridine-3-carbaldehyde 4 - [(6-Trifluoromethyl-pyridin-3-ylmethyl) -amino] -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) 20 amide (72 mg , 31.4%) as a white solid; EM-ES-HR m / e calculated for the C19H20F3N7O2S (M + H) + = 468.1424; found = 468.1424.

Example 85

Synthesis of 4- (4-fluor-3-trifluoromethyl-benzoylamino) piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide

image5 OR

image5 OF

image5 OR image5 Cl

HO N image5 image5 image5 F

N

H F +

F S NNH2 F N

F O N F

image109

A suspension of the suspension is stirred at 25 ° C overnight. 4-Amino-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide salt (obtained in the manner described in Example 83, 580

10 mg, 1.37 mmol), 4-fluor-3-trifluoromethyl-benzoyl chloride (261 ml, 1.64 mmol) and triethylamine (573 µl, 4.11 mmol) in methylene chloride (15 ml). Then dilute the reaction mixture with water and extracted with acetate ethyl. The organic phase is washed with an aqueous solution.

15 saturated sodium chloride and a saturated aqueous solution of sodium bicarbonate, dried with sodium sulfate, filtered and It is concentrated under vacuum. By flash chromatography (gel Merck silica 60, 230-400 mesh, gradient elution: from

a 3: 7 mixture of ethyl acetate / hexanes 100% acetate

ethyl) (4- (4-fluor-3-trifluoromethyl-benzoylamino) piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide (21 mg, 30 , 6%) as a solid matte white; EM-ES-HR m / e calculated for the C20H18F4N6O3S

5 (M + H) + = 499.1170; found = 499.1170. Example 86 Synthesis of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl)

3- [2- (3-Trifluoromethyl-phenoxy) -ethylamino] pyrrolidine-1-carboxylic acid amide

image5 OR image5 OR

OO

image5

OR image5 OR

N

N

image5 N image5

H

NH2 + HN NH N

image5 NH

N image5

S

N

S

N image5

N

OR

10 Step 1: A mixture of 7-methoxy-thiazole [5,4d] pyrimidin-2-ylamine (1.0 g, 5.50 mmol) and tetrahydrofuran is treated (1 L) with pyridine (1.3 g, 16.48 mmol). The mixture is stirred reactant at 25 ° C for 30 min. Next is about The reaction mixture slowly with a solution of triphosgene (880 mg, 2.96 mmol) in tetrahydrofuran (5 ml) and then with (3R) - (+) - 3- (tert-butoxycarbonyl) amino-pyrrolidine (1.74 g, 9.34 mmol). The mixture is kept under stirring at 25 ° C overnight. Then the reaction is interrupted by 20 addition of a 1N aqueous solution of hydrochloric acid. Be Extract the aqueous phase with ethyl acetate. The phase is washed organic with a 2N aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and concentrated in vacuo, 25 obtaining the [1- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcar

bamoyl) -pyrrolidin-3-yl] tert-butyl carbamate (1.75 g, 81%) in the form of beige solid; EM-LR of C16H22N6O4S (M + H) + a m / z = 394. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

image5 OR image5 image5 image5 image5

OO image5 OR

CF3COOH

N image5

H

N

N

H

NNH N

image5 NH2

N image5

SN

N

SN

N

OR

OR

5 Step 2: A mixture of tert-butyl [1 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -pyrrolidin-3-yl] carbamate is stirred at 25 ° C (3.4 g, 8.63 mmol) in acid trifluoroacetic (25 ml). Then the 10 reaction mixture under vacuum, obtaining a red oil. This oil is crushed with ether, obtaining the salt of the (S) -3-Amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide trifluoroacetic acid (3.5 g, 99%) in slightly brown solid shape.

image5 OR image5 image5 Br image5

CF3COOH

N

image5 OR

H

N

NH2

N

NH

Or CF3

H

N

SN

+

N

image5 N image5

N

OR image5 CF3

OR

SN

N

OR

fifteen Step 3: A mixture of the (S) -3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide (300 mg, 0 , 74 mmol) in N, N-dimethylformamide (5 ml) with N, N-diisopropylethylamine (285 mg, 2.20 20 mmol) and 1- (2-bromoethoxy) -3- (trifluoromethyl) -benzene (220 mg, 0.81 mmol). The reaction mixture is kept under stirring.

at 80 ° C for 1 h. Then the reaction mixture was poured

over water The aqueous phase is extracted with ethyl acetate. Be wash the organic phase with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and Concentrate with vacuum. By high liquid chromatography In preparation, the 3- (2- (3-trifluoromethylphenoxy) -ethylamino] -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide (28 mg, 8%) in slightly brown solid form; EM-LR of the C20H21F3N6O3S (M + H) + at m / z = 482. The NMR spectrum obtained from the sample is

10 compatible with the structure of the compound. Example 87 Synthesis of (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl)

(R) -3- (4-Fluoro-3-trifluoromethyl-benzylamino) pyrrolidine-1-carboxylic acid amide

image5 OR image5 OR

OO

image5

OR image5 OR

N

N

image5 N image5

H

NH2HN NH N

+

NH

N image5

S

N

S

N image5 image5

N

OR

fifteen Step 1: a phenyl (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -carbamate solution (1.5 g, 0.0049 mol) in acetonitrile (80 ml) with pyrrolidin-3 (R) -butyl tert-butylcarbamate (0.92 g, 0.049 mol). It heats up 20 the reaction mixture at reflux for 1 h. Cools to 25oC and concentrated in vacuo. The residue is crushed with ether, filtered and dried under vacuum, obtaining [1- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -pyrrolidin3 (R) -yl] -carbamate tert-butyl (1.99 g, 99%); EM-LR of C16H22N6O4S (M + H) at m / z = 395.

image5

image5 OR

image5 OO O

CF3COOH NHN image5 NH

N image5 NH N

NH2S N image5

NN S

N image5 image5 ON

OR

Step 2: A mixture of [1 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -pyrrolidin-3 (R) -yl] -carbamide of tert-butyl (11) is stirred for 2 h , 7 g, 0.029 moles) and

5 trifluoroacetic acid (50 ml). The mixture is concentrated. Reactant with vacuum. The resulting residue is crushed with ether and dried under vacuum, obtaining the acid salt 3-Amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide trifluoroacetic acid (14.5

10 g, 94.1%) in the form of a matt white solid.

image5 OR

CF3COOH N image5 OR

HN image5 FNH2N image5

N H

HNS N image5 image5 N NN image5 CF3O S

NO N

Step 3: a suspension of the acid salt is treated 3-Amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-215 yl) -amide trifluoroacetic acid (2.35 g, 5.8 mmol) in methanol (50 ml) with N, N-diisopropylethylamine (1.5 ml, 8.6 mmol). The resulting mixture is stirred at 25oC for 30 min. Then the mixture is treated reactant with 4-fluor-3- (trifluoromethyl) benzaldehyde (1.34 20 g, 6.96 mmol) and then with toluene (50 ml). Stir the resulting mixture at 60 ° C for 1 h and concentrated with empty. More toluene (200 ml) is added. The mixture is stirred

reactant for 15 min and concentrated in vacuo. Be repeat this procedure a few more times until the reaction mixture be homogeneous when dissolved in Toluene. After a final concentration to remove the 5 toluene, the reaction mixture is diluted with dichloroethane (100 ml) and treated with acetic acid (351 mg, 5.8 mmol) and sodium triacetoxyborohydride (3.7 g, 17.4 mmol). It keeps the reaction mixture resulting in stirring at 25 ° C for one night. The reaction mixture was poured into water and 10 extracted with ethyl acetate. The organic phases meet, washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of chloride sodium, dried with sodium sulfate, filtered and dried concentrate with vacuum. By flash chromatography (silica gel Merck 15 60, 230-400 mesh, gradient elution of a mixture

1: 1 ethyl acetate / hexanes 100% ethyl acetate) (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained of (R) -3- (4-fluor-3-trifluoromethyl-benzylamino) -pyrrolidine-1-carboxylic acid (1.44 g, 52.8%) as a solid

20 sparkling; EM-ES-HR m / e calculated for C19H18F4N6O2S (M + H) + = 471,1221; found = 471.1221. In a similar way the compounds of the Examples 88-89 as follows:

Example 88

image110

From the 3-amino5 pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide trifluoroacetic acid salt and (4-fluor-3- chloride) trifluoromethyl-benzoyl is obtained ((R) -3- (4-fluor-3-trifluoromethyl-benzoylamino) -pyrrolidine-1 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide) -carboxylic (72 mg, 31.4%) in the form of white solid (48 mg, 39%); EM-ES-HR m / e calcu

10 side for C19H16F4N6O3S (M + H) + = 507.0833; found = 507.0837. Example 89

image110

From the (S15-3-amino-pyrrolidine-1-carboxylic acid (715 methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide salt of the trifluoroacetic acid (obtained in example 86) Y

from 4-fluor-3-trifluoromethyl-benzoyl chloride the

(S) 7-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

3- (4-fluor-3-trifluoromethyl-benzoylamino) -pyrrolidine-1-carbo

xyl in the form of white solid (18 mg, 10%); EM-ES-HR m / e 5 calculated for C19H16F4N6O3S (M + H) + = 485,1014; found =

485,1016.

Example 90

Synthesis of 4-fluor-N- {2- [3- (7-methoxy-thiazolo [5.4

d] pyrimidin-2-yl) -ureido] -ethyl} -3-trifluoromethyl-benzamide

image5 O o

O o

O O NN NNH H

NH2 +

NH S

N

N

SN H H2N O

10

A solution of 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine (233 mg, 1.28 mmol) and pyridine is treated at 25 ° C (310 µl, 3.53 mmol) in tetrahydrofuran (6 ml) with a solution of triphosgene (190 mg, 0.64 mmol) in tetrahydrofu

15 rano (2 ml) and then with (2-tert-butoxycarbonylaminoethyl) -carbamic acid (225 mg, 1.40 mmol). The mixture is stirred reactant at 25oC overnight. Then you treat the reaction mixture with a 1N aqueous solution of hydrochloric acid and stirred at 25 ° C for an additional 30 min. Then

20 the resulting precipitate is collected by filtration and washed with a 1N aqueous solution of hydrochloric acid and with ether of diethyl, obtaining the tert-butyl {2- [3- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -ureido] -ethyl} -carbamate (170 mg, 36.8%) as a pink solid; EM-LR of C14H20N6O4S (M + H) + a

25 m / z = 369.

image111

image5

image5 OR

OR image5 OR image5 OR

image5 F

N H

N

NH

H

image5 NH N

N image5

image5 N

N image5

CF3

S

N

N

S

N

HN

OR

HO

OR

A solution of tert-butyl {170- [3- (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -ureido] -ethyl} -carbamate (170) 5 mg, 0.46 mmol) with trifluoroacetic acid (80 µl, 0.57 mmoles). The reaction mixture is stirred at 25 ° C for 1 h. The reaction mixture is concentrated in vacuo, crushed with diethyl ether, collected by filtration and dried with empty. A portion of the acid salt is treated at 25 ° C Trifluoroacetic acid resulting from the 3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4d] pyrimidin-2-yl) -amide (88 mg, 0.23 mmol) in methylene chloride with 4-fluor-3- (trifluoromethyl) benzoyl chloride (70 ml, 0.46 mmoles). The resulting solution is stirred at 25 ° C for one 15 night By flash chromatography (Merck silica gel 60, 230-400 mesh, gradient elution of a 3: 1 mixture of ethyl acetate / hexanes 100% ethyl acetate) is obtains 4-fluor-N- {2- [3- (7-methoxy-thiazolo [5,4-d] pyrimidin2-yl) -ureido] -ethyl} -3-trifluoromethyl-benzamide (25 mg, 11.8 %) 20 in the form of white solid; EM-ES-HR m / e calculated for the

C17H14F4N6O3S (M + H) + = 459.0857; found = 459.0862.

Example 91

Synthesis of 1- [2- (4-fluor-3-trifluoromethyl-benzylamine

no) -ethyl] -3- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -urea

image5 OR image5 OR

F image5 OF

F

N

H

N

HO

N image5

F + H

H

F

F

SN image5 N

F

OR

NH2

image112

To a solution of the trifluoroacetic acid salt of amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide (176 mg, 0.46 mmol) in methanol (6 ml) is added at 25 ° C 4-fluor-3- (trifluoromethyl) -benzaldehyde (90 mg, 0.46 mmol) and sodium triacetoxyborohydride (293 mg, 1.38 mmol). The solution is stirred resulting at 25oC overnight. Next is about 10 the reaction mixture with triethylamine (200 ml, 1.44 mmol) and stir for another 24 h. Then the mixture is concentrated Reactant with vacuum. By flash chromatography (gel Merck silica 60, 230-400 mesh, 95/5 gradient elution methylene chloride / methanol) is obtained 1- [2- (4-fluor-3

Trifluoromethyl-benzylamino) -ethyl] -3- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -urea (37 mg, 18%); ES-ES-HR m / e calculated for C17H16F4N6O2S (M + H) + = 445,1065; found = 445.1065.

Example 92 Synthesis of 3- (7-methoxy-thiazolo [5,4-d] pyrimidin-2il) -1-methyl-1- [2- (3-trifluoromethyl-phenoxy) -ethyl] urea

image5 OR image5 CF3 Br image5

OR image5 CF3 image5 NH

5 Step 1: Treat a mixture of the hydrochloride salt of the methylamine (380 mg, 5.57 mmol) and tetrahydrofuran (10 ml) with N, N-diisopropylethylamine (1.44 g, 11.15 mmol) and 3- (2-bromoethoxy) benzotrifluoride (300 mg, 1.11 mmol). The reaction mixture is kept under stirring at reflux for 2 d.

10 The reaction is then interrupted by the addition of water. The aqueous phase is extracted with ethyl acetate. Wash the organic phase with a saturated aqueous chloride solution sodium, dried with magnesium sulfate, filtered and Concentrate with vacuum. By flash chromatography (silica gel

Merck 15 60, 230-400 mesh, 95/5 methylene chloride / methanol) methyl- [2- (3-trifluoromethyl-phenoxy) -ethyl] -amine is obtained (110 mg, 45%) as a yellow solid. NMR spectrum obtained from the sample is compatible with the structure of the compound.

image5 OR

image5 OR image5 CF3 image5 OR image5 CF3 image5 N

NH cl

twenty Step 2: a mixture of triphosgene (750 mg, 2.51 mmol) and methylene chloride (10 ml) under a nitrogen atmosphere with pyridine (400 mg, 5.00 moles) and then slowly add a solution of 25 methyl- [2- (3-trifluoromethyl-phenoxy) -ethyl] amine (110 mg, 0.50

mmoles) in methylene chloride (2 ml) from a funnel decanting The reaction mixture is stirred at 25 ° C for one night. The reaction mixture is then washed with a 1N aqueous solution of hydrochloric acid and a solution

5 saturated aqueous sodium chloride, dried with sulfate magnesium, filtered and concentrated in vacuo, obtaining methyl- [2- (3-trifluoromethyl-phenoxy) -ethyl] amine-1carbonyl chloride (0.90 g, 64%) as a golden yellow oil.

image5 CF3O image5 OR image5 OR

image5 N image5 image5 N image5 image5 image5 ON

image5 OR image5 CF3 N

HNH2 + Cl N N

SN S NN O

10 Step 3: treat at 25 ° C under a nitrogen atmosphere mixture of 7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylamine (60 mg, 0.30 mmol) and tetrahydrofuran (6 ml) with sodium hydride (20 mg, 0.40 mmol). The reaction mixture is stirred at 65 ° C. for 30 min. The reaction mixture is then treated with

15 N, N-diisopropylethylamine (130 mg, 1.00 mmol) and chloride methyl- [2- (3-trifluoromethyl-phenoxy) -ethyl] amine-1-carbonyl (90 mg, 0.32 mmol). The mixture is stirred at 65 ° C for one night. The reaction mixture is then concentrated with vacuum, diluted with water and extracted with ethyl acetate.

20 The organic phase is washed with a 2N aqueous solution of acid hydrochloric and a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and concentrated with empty. By flash chromatography (Merck silica gel 60, 230-400 mesh, 95/5 methylene chloride / methanol) is obtained

25 3- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -1-methyl-1- [2- (3

trifluoromethyl-phenoxy) -ethyl] urea (40 mg, 28%) in the form of slightly brown solid; EM-LR of C17H16F3N5O3S (M + H) + at m / z = 427. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 93

Synthesis of (7-methoxy-thiazolo [5,4-b] pyridine-2-yl)

4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperi acid amide

dyna-1-carboxylic

image113

10 Step 1: to a mixture of 4-methoxy-3-nitropyridine (5.0 g, 32.44 mmol) and ethanol (100 ml) a catalyst is added 10% palladium on charcoal (200 mg). The mixture resulting in stirring with hydrogen pressure (50 psi) at room temperature for 6 h. By CCF (acetate

50% ethyl in hexane) it is confirmed that it has been consumed Completely the starting material. By filtration through of Celite to separate the catalyst and concentration is obtains 3-amino-4-methoxypyridine (4.0 g, 32.44 mmol, yield: 100%) in the form of dark red oil.

image5 OR image5 image5 OR image5 NH2

NH2

N NCl

twenty

Step 2: to a stirred mixture with magnetic rod 3-amino-4-methoxypyridine (4.45 g, 35.89 mmol) and 12N HCl (25 ml) cooled in an ice bath is added peroxide

hydrogen (5.3 g, 46.65 mmol, 30% solution). Is left slowly heat the reaction mixture to temperature ambient and stir for 1 h. By TLC (ethyl acetate at 50% in hexane) it is found that the starting material has been 5 consumed completely. The reaction mixture was poured slowly over a saturated solution of sodium bicarbonate (400 ml) to neutralize it and extract with ethyl acetate. The resulting organic phases are washed with a solution saturated with sodium chloride and dried with magnesium sulfate.

By filtration and concentration, 3-amino-2-chloro-4-methoxypyridine (4.56 g, 28.77 mmol, yield: 80%) is obtained in Orange solid form.

image5 OH OR image5 image5 OO image5 NH2 CF3

H H

N image5 NN + Cl N OH

N Cl

S O

N Cl

CF3

Step 3: to a stirred mixture with magnetic rod

4-Hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1carbonyl chloride (465 mg, 1.51 mmol) and acetone (15 ml) are added ammonium thiocyanate (105 mg, 1.39 mmol). Stir the reaction mixture at reflux for 30 min. The 3-amino-2-chloro-4 methoxypyridine (200 mg, 1.26 mmol) and

20 stirring at reflux continues overnight. By CCF (50% ethyl acetate in hexane) it is found that the Starting material has been completely consumed. Is poured the reaction mixture on water and the aqueous phase is extracted with ethyl acetate. The organic phases are washed out

tes with 2N HCl (2X) and a saturated solution of sodium chloride and dried with magnesium sulfate. By purification by Flash chromatography gives 1- (2-chloro-4-methoxy-pyridin-3-yl) -3- [4-hydroxy-4- (3-trifluoromethylphenyl) -piperidine-1

5 carbonyl] -thiourea (100 mg, 0.20 mmol, yield: 16%) in slightly yellow solid form. (EM-LR of C20H20ClF3N4O3S (M + H) + at m / z = 488. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

image5 OH image5 OO image5 CF3

H HN image5 N image5 NN H image5 OH N image5

S O S N CF3N

N Cl O

10 Step 4: to a stirred mixture with magnetic rod 1- (2-Chloro-4-methoxy-pyridin-3-yl) -3- [4-hydroxy-4- (3-trifluoromethylphenyl) -piperidine-1-carbonyl] -thiourea (100 mg, 0.20 mmol) and THF (10 ml) is added sodium hydride (10 mg, 0.25 15 mmol, 60% dispersion in mineral oil). Stir the refluxing reaction mixture overnight. By CCF (80% ethyl acetate in hexane) it is found that the Starting material has been completely consumed. Is poured the reaction mixture on water and the aqueous phase is extracted 20 with ethyl acetate. The resulting organic phases are washed with 2N HCl (2X) and a saturated chloride solution. sodium and dried with magnesium sulfate. By purification Flash chromatography gives 4-hydroxy-4- [325 (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-b] pyridine-2-yl) -amide (20 mg , 0.04

mmoles, yield: 22%) as a slightly solid yellow. (LRMS of C20H19F3N4O3S (M + H) + at m / z = 452. Example 94

image5 OR image5

image5 F

OR image5

F

F

N image5 N image5

N

image5 OR image5

image5 OR image114

N

H

NH

NO

S

N

N

F

N

H

F

S

NF

5 A mixture of 8-trifluor-1,2,3,4-tetrahydroisoquinoline (30 mg, 0.15 mmol, RO4993861-000) in acetonitrile (5 ml) is treated with (7-methoxy-thiazolo [5,4-d ] phenyl pyrimidin-2-yl) carbamate (45 mg, 0.15 mmol). The mixture is stirred 10 at reflux for 2 h. The mixture is then poured reactant on a saturated aqueous solution of sodium bicarbonate. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and 15 concentrate under vacuum. By flash chromatography (silica gel Merck 60, 230-400 mesh, 98/2 methylene chloride / methanol) (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained of 8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (23 mg, 38%) as a slightly solid 20 brown LRMS of C17H14F3N5O2S (M + H) + at m / z = 409. The spectrum NMR obtained from the sample is compatible with the structure of the compound.

25

Example 95

image5 OR image5 image5 OR image5 image5

image5 OR image5

NO

OR image5

N

image5 F

N

N image5 N

+

N

N

S

N

F

N

F

H

S

N F

F

F

A mixture of 6-trifluor-1,2,3,4-tetrahydroisoquinoline (50 mg, 0.25 mmol) and acetonitrile (10 ml) is treated with Phenyl 5 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -carbamate 745 mg, 0.25 mmol). The mixture is stirred at reflux for 2h The reaction mixture is then poured onto a saturated aqueous sodium bicarbonate solution. The aqueous phase with ethyl acetate. The organic phase is washed 10 with a saturated aqueous solution of sodium chloride, dry With magnesium sulfate, it is filtered and concentrated in vacuo. By flash chromatography (Merck silica gel 60, 230-400 mesh, 98/2 methylene chloride / methanol) (6-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained from acid 6

15 trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic (15 mg, 15%) as a white solid. EM-LR of the C17H14F3N5O2S (M + H) + at m / z = 409. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 96 Synthesis of (3-Chloro-phenyl) - [4- (7-methoxy-thiazolo [5,4d] pyrimidin-2-ylcarbamoyl) -piperazin-1-yl] -methyl acetate

Br

Cl image5

Cl image5

COOCH3

COOCH3

Step 1: Boil at reflux for three days a mixture of (3-chloro-phenyl) -methyl acetate (2.0 g, 10.8 mmol), N-bromosuccinimide (1.95 g, 11.0

5 mmol) and 3 drops of hydrobromic acid (48% solution) and chloroform (100 ml). Additional amounts of Nbromosuccinimide and hydrobromic acid are added to make it Complete the reaction. The reaction mixture is concentrated to dryness, it is collected in methylene chloride and introduced into

10 a column of silica gel. By elution with acetate 10% ethyl in hexanes gives the bromine- (3-chloro-phenyl) methyl acetate (1.95 g, yield: 69%) as colorless oil The NMR spectrum obtained from the sample is compatible with the structure of the compound.

image5 OR

Br

OR image5

image5 OR

image5 COOCH3

OR image5

N image5 image5 image5 NH

N

Cl

N

N image5 image5 N

N

COOCH3

N

N

N

H +

SN

H

S

Cl

N

fifteen Step 2: stir at room temperature for 30 minutes a mixture of the piperazine-1-carboxylic acid (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide trifluoroacetate salt (1.56 g, 3.82 mmol), diisopropylethylamine (2.7 20 ml, 15.5 mmol) and N, N-dimethylformamide (15 ml). This mixture is added potassium carbonate (0.8 g, 5.8 mmol) and bromine- (3-chloro-phenyl) -methyl acetate (1.0 g, 3.8 mmol) and The resulting mixture is stirred at room temperature for one night. By filtration and concentration a

solid, which is dissolved in methanol and absorbed in 2 g of silica gel. The silica gel is introduced into a 120 g Isco column eluted using 0 • 5% methanol in methylene chloride, obtaining (3-chloro-phenyl) - [4- (7

Methyl methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-yl] -acetate in the form of white powder; EM-LR of C20H21ClN6O4S (M + H) + at m / z = 477. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

Example 97 Acid 10 (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4- [1- (3-Chloro-phenyl) -2-hydroxy-ethyl] -piperazine-1-carboxylic

image115

To a mixture of (3-chloro-phenyl) - [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-yl] -acetate 15 methyl (100 mg, 0.21 mmol) and tetrahydrofuran (3 ml) are given add lithium aluminum hydride at 0oC (25 mg, 0.66 mmoles). The mixture is heated to room temperature and stir for two hours. The EM-LC analysis indicates that there is a mixture of starting material and product. The 20 mix in Feiser conditions and the product is purified in crude by reverse phase HPLC, obtaining 4- (1- (3-chloro) (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide

phenyl) -2-hydroxy-ethyl] -piperazine-1-carboxylic acid in the form of

white powder; LRMS of C19H21ClN6O3S (M + H) + at m / z = 449. The NMR spectrum obtained from the sample is compatible with the compound structure

Example 98

Acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

4- [2-Methoxy-1- (3-trifluoromethyl-phenyl) -ethyl] -piperazine-1

carboxylic

image5 Br

F3C image5 F3CCOOCH3 COOCH3

Step 1: Boil at reflux for two

10 days a mixture of (3-trifluoromethyl-phenyl) -methyl acetate (6.0 g, 25.9 mmol), N-bromosuccinimide (9.2 g, 51.7 mmoles), a few drops of hydrobromic acid (48% solution) and chloroform (250 ml). The reaction mixture is concentrated to dryness, it is collected in methylene chloride and introduced into

15 a column of silica gel. By elution with acetate 5% ethyl in hexanes gives bromo- (3-trifluoromethylphenyl) -methyl acetate (3.0 g, yield: 39%) as of colorless oil. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

image5 Br

image5 OR

image5 OR

F3C

COOCH3

image5 ON

image5 ON

+

NH

N

CF3

COOCH3

Step 2: stir at room temperature for a

overnight a mixture of tert-butyl piperazine-1-carboxylate

(1.80 g, 9.68 mmol), potassium carbonate (2.0 g, 14.5

mmol), bromo- (3-trifluoromethyl-phenyl) -methyl acetate (3.0 g, 9.65 mmol) and N, N-dimethylformamide (40 ml). By concentration a raw material is obtained that is distributed between methylene chloride and water. The organic phase is dried with 5 magnesium sulfate and concentrate, obtaining an oil. Be introduce the resulting crude oil into an Isco column 120 g and elute with 20% ethyl acetate in hexanes, obtaining 4- [ethoxycarbonyl- (3-trifluoromethyl-phenyl) methyl] -piperazine-1-carboxylic acid tert-butyl ester (3.0 g,

10 yield: 74%) as a colorless oil. The spectre NMR obtained from the sample is compatible with the structure of the compound.

image5 OR

image5 OR image5 ON

image5 ON

N NCF3 CF3

COOCH3 OH

Step 3: to a solution of 4- [ethoxycarbonyl- (3

Tertbutyl trifluoromethyl-phenyl) -methyl] -piperazine-1-carboxylate (2.10 g, 5.05 mmol) in tetrahydrofuran (30 ml) is it adds drip at 0oC lithium aluminum hydride (LAH, 1M in tetrahydrofuran, 7.57 ml, 7.57 mmol). Stir the Mix at 0oC for two hours. Excess LAH is removed

20 with ethyl acetate and the mixture is stirred with sodium sulfate Dehydrated for 10 minutes. The suspension is filtered and the filtered liquid is partitioned between ethyl acetate and water. The organic phase is dried with magnesium sulfate. By filtration and concentration a raw material is obtained, which is

25 introduced into a column of silica gel. By elution with

acetate

from ethyl to the 40% in hexanes be gets he 4- [2

hydroxy-1- (3-trifluoromethyl-phenyl) -ethyl] -piperazine-1

carboxylate

from tert-butyl (1.4 g, performance: 74 %) in

shape

from oil colorless. He spectrum NMR obtained from the

5

Sample is compatible with the structure of the compound.

image5 OR image5 OR

image5 ON image5 ON

N NCF3

CF3 OH

OR

Step 4: to a mixture of tert-butyl 4- [2-hydroxy-1- (3-trifluoromethyl-phenyl) -ethyl] -piperazine-1-carboxylate (200 mg, 0.53 mmol), tetrahydrofuran (5 ml) and N, N-dimethylfor

10 mamida (5 ml) are added at 0oC sodium hydride (60% in mineral oil, 70 mg, 1.75 mmol) and then the iodomethane (230 mg, 1.62 mmol). The mixture is stirred at 0 ° C. for three hours The reaction is interrupted with a saturated aqueous solution of ammonium chloride and the

15 mixture between ethyl acetate and water. The organic phase is dried with magnesium sulfate. By filtration and concentration, you get a crude oil, which is introduced into a column silica gel By elution with 50% ethyl acetate in hexanes, 4- [2-methoxy-1- (3-trifluoromethyl-phenyl) is obtained

Tert-butyl ethyl] -piperazine-1-carboxylate (190 mg, yield: 92%) as a colorless oil. The spectre NMR obtained from the sample is compatible with the structure of the compound.

image5 OR image5 ON

image116 HN NN

CF3 or CF3

OR

Step 5: stir at room temperature for a hour a mixture of tert-butyl 4- [2-methoxy-1- (3-trifluoromethyl-phenyl) ethyl] -piperazine-1-carboxylate (150 mg, 0.387

5 mmol) in trifluoroacetic acid alone (3 ml). The mix to dryness and with high vacuum pump, obtaining the 1- [2-Methoxy-1- (3-trifluoromethyl-phenyl) ethyl] -piperazine trifluoroacetate as an oil. This material is used in the next step without further purification.

CF3COOH image5 OO image5 image5 OR image5 OO image5 OR image5 HN image5 NN N image5 image5 NNN NN

+

CF3

NHSN H CF3SNO

10

Step 6: heat at 70 ° C for ten minutes a

1- [2-methoxy-1- (3-trifluor trifluoroacetate mixture

methyl-phenyl) -ethyl] -piperazine (160 mg, 0.40 mmol), diiso

15 propylethylamine (0.35 ml, 2.0 mmol) and acetonitrile (10 ml). The above solution is cooled to room temperature and it is add the (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -carbamate of phenyl (120 mg, 0.40 mmol). The mixture is stirred at reflux for three hours EM-LC analysis shows that the

20 starting material has been completely consumed. The reaction mixture is concentrated and the material is purified in

crude by reverse phase HPLC, obtaining (7-methoxy

4- [2-Methoxy-1 (3-trifluoromethyl-phenyl) -ethyl] -piperazine-1-carboxylic acid thiazolo [5,4-d] pyrimidin-2-yl) -amide (81 mg, yield: 41%) in the form of white powder. EM-LR of C21H23F3N6O3S (M + H) + at m / z = 497. The NMR spectrum obtained from

5 the sample is compatible with the structure of the compound. Example 99 (7-Methoxy-5-methylsulfanyl-thiazolo [5,4-d] pyrimidin-2

4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid

image5 OH image5 OH OR

+

N

N

image5 O SNOH SNOH N

10 Step 1: 4,6-dihydroxy-2-methylthiopyrimidine (10.0 g, 63.22 mmol) on nitric acid is added at 0 ° C for 0 h smoker (30 ml). The red solution is stirred at 0 ° C for 1 h more and then poured on ice, obtaining a solid 15 slightly brown, which is filtered and washed with water and ether of diethyl. The solid is dried under vacuum, obtaining 4,6-dihydroxy-2-methylthio-5-nitropyrimidine (9.30 g, 72%) as of slightly brown solid. EM-LR of C5H5N3O4S (M + H) + at m / z = 203. The NMR spectrum obtained from the sample is compatible 20 with the structure of the compound.

image5 OH OR image5 Cl O

+ +

N

image5 N

ON

image5 OS NOH N

S NCl

Step 2: Boil at reflux for 1 h a mixture of 4,6-dihydroxy-2-methylthio-5-nitropyrimidine (9.30 g, 45.81 mmol), phosphorus oxychloride (40 ml) and diethylaniline (12 ml). After a partial concentration

5 by evaporation the liquid is poured on ice, obtaining a brown solid that is filtered and washed with water. be dry the solid under vacuum, obtaining 4,6-dichloro-2-methylthio-5-nitropyrimidine (10.5 g, 95%) as a solid Brown. LRMS of C5H3Cl2N3O2S (M + H) + at m / z = 240. The spectrum

10 NMR obtained from the sample is compatible with the structure of the compound.

image5 Cl O image5 image5 image5 OO image5

+ +

N N

NO NO S NCl

S NCl

Step 3: A mixture of 4,6-dichloro-2-methylthio5-nitropyrimidine (5.25 g, 21.88 mmol) and methanol (40 ml) is treated 15 with sodium methoxide (1.3 g, 24.06 mmol). The mixture is stirred at room temperature for 3 h. Then poured the reaction mixture on ice, obtaining a solid Brown that is filtered and washed with water. The solid dries under vacuum, obtaining 4-chloro-6-methoxy-2-methylthio-5

20 nitropyrimidine (4.40 g, 85%) as a brown solid. EMLR of C6H6Cl1N3O3S (M + H) + at m / z = 235. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

image5 image5 OO image5

image5 image5 OO image5

+

+

N

N

NO

NO

S NCl

S N SCN

Step 4: A mixture of 4-chloro-6-methoxy-2-methylthio-5-nitropyrimidine (4.40 g, 18.68 mmol) and acid is treated acetic acid (30 ml) with ammonium thiocyanate (2.84 g, 37.37

5 mmol). The mixture is stirred at 85 ° C for 6 h. After a partial evaporation the liquid is poured on ice, obtaining a brown solid that is filtered and washed with Water. The solid is dried under vacuum, obtaining 4-methoxy-2-methylthio-5-nitro-6-thiocyanate-pyrimidine (2.20 g, 46%) in

10 form of brown solid. LRMS of C7H6N4O3S2 (M + H) + at m / z =

258. The NMR spectrum obtained from the sample is compatible with The structure of the compound.

image5 image5 OO image5 image5 OR

+

N

image5 N

O n

N

NH2

S

S NSCN SN

Step 5: cool a mixture with a water-ice bath

4-methoxy-2-methylthio-5-nitro-6-thiocyanate-pyrimidine (2.20 g, 8.53 mmol) in acetic acid (30 ml) and added in portions of iron powder (1.43 g, 25.58 mmol). One time After the addition, the mixture is stirred at 60 ° C for 4 h. The reaction mixture is cooled to room temperature,

20 filtered and poured on ice, obtaining a solid

slightly brown, which is filtered and washed with water and ether of diethyl. The solid is dried under vacuum, obtaining 7-methoxy-5-methylsulfanyl-thiazolo [5,4-d] pyrimidin-2-ylamine (1.60 g, 82%) as a slightly brown solid. EM-LR

5 of C7H8N4OS2 (M + H) + at m / z = 228. The NMR spectrum obtained from The sample is compatible with the structure of the compound.

image117 OR

image118 OH

image5 OR

Cl N image5 OH

N NNH2 +

image5 S

F

F FF

F F

Step 6: in nitrogen atmosphere it is treated at 25 ° C

10 stirred mixture with magnetic rod of 7-methoxy-5-methylsulfanyl-thiazolo [5,4-d] pyrimidin-2-ylamine (500 mg, 2.19 mmol) and tetrahydrofuran (20 ml) with sodium hydride (60% suspension in mineral oil, 265 mg, 6.58 mmol). Be Stir the reaction mixture at 50 ° C for 1 h. To continuous

The reaction mixture is cooled to room temperature and treated with N, N-diisopropylethylamine (850 mg, 6.58 mmol) and 4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carbonyl chloride (810 mg, 2.63 mmol). The mixture is stirred reactant at room temperature for 3 d. Then I know

20 concentrate the reaction mixture under vacuum, pour over water and extracted with ethyl acetate. The phase is washed organic with a 2N aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium chloride, dried with

magnesium sulfate, filtered and concentrated in vacuo. By

flash chromatography (Merck silica gel 60, 230-400 mesh,

98: 2 methylene chloride / methanol) (7-methoxy-5-methylsulfanyl-thiazolo [5,4-d] pyrimidin-2-yl) -amide is obtained 4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic

5 (375 mg, 34%) as a red solid. EM-LR of C20H20F3N5O3S2 (M + H) + at m / z = 499. The NMR spectrum obtained from the sample is compatible with the structure of the compound.

Example 100 (5-hydroxy-7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 10 4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1 carboxylic acid

OR image5

OR image5

image5 OR

image5 OR image5 N

image5 OH

image5 N

image5 OH

N

N

N N

NN S

S

image5 S N

image5 image5 S image5 N OO

F

F

F

F F

F

Step 1: cool a mixture with a water-ice bath stirred with a magnetic rod of 4-hydroxy-4- [3 (trifluoromethyl) phenyl] piperidine-1- (7-methoxy-5-methylsul15 fanyl-thiazolo [5,4-d] pyrimidin-2-yl) -amide carboxylic (375 mg, 0.75 mmol) and methanol (20 ml) and treated with sodium tungstate dihydrate (135 mg, 0.04 mmol) and then with peroxide hydrogen (30% solution, 10 ml). The mixture is heated 20 reactant at room temperature and stirred for 2 h. The reaction mixture was poured into water and extracted with methylene chloride The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with sulfate magnesium, filtered and concentrated in vacuo, obtaining

4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide (251 mg, 63%) in the form of red solid. EMLR of C20H20F3N5O5S2 (M + H) + at m / z = 499. The NMR spectrum obtained

The nest of the sample is compatible with the structure of the compound.

image5 OR image5

image5 OR

image5 OR image5

N

image5 OH

N

image5 OR

N N

N

image5 OH

N

S

image5 image5 S image5 N

N N

O o

S

HO N F

F FF

F F

Step 2: a stirred mixture is treated with a rod 4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo [5,410 d] pyrimidin-2-yl) -amide (250 mg, 0.47 mmol), THF (10 ml) and water (5 ml) with a 2N aqueous solution of KOH (0.5 ml, 0.94 mmol). The reaction mixture is stirred at 75 ° C. for 4 h. The reaction mixture is cooled to temperature At room temperature, it is poured onto water and extracted with methylene The organic phase is washed with an aqueous solution. saturated with sodium chloride, dried with magnesium sulfate, dried filter and concentrate in vacuo, obtaining 4 (hydroxy-7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide

Hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (32 mg, 15%) as a white solid. EM-LR of C19H18F3N5O4S2 (M + H) + at m / z = 469. The NMR spectrum obtained from

The sample is compatible with the structure of the compound.

Example 101

Acid (7-methoxy-thiazolo [5,4-b] pyridin-2-yl) -amide 3- (4-fluor-3-trifluoromethyl-benzylamino) -pyrrolidine-1-carboxylic acid

OR image5

image5 OR image5 image5 OR

image5 NH2

image5 OR

OR

N

image5 OR

+ Cl N

NN image5

NO

H

N Cl

S NO image5

H

N

H

5 Step 1: a nitrogen atmosphere is treated at 25 ° C stirred mixture with magnetic rod of tert-butyl (1-chlorocarbonylpyrrolidin-3-yl) carbamate (820 mg, 3.30 mmol) and acetone (15 ml) with ammonium thiocyanate (240 mg, 10 3.15 mmol). The reaction mixture is stirred at reflux for 30 min. Then the mixture is reacted- te with 3-amino-2-chloro-4-methoxypyridine (440 mg, 2.78 mmoles). The reaction mixture is kept boiling at reflux overnight. Then the mixture is concentrated 15 reactant under vacuum, poured into water and extracted with ethyl acetate. The organic phase is washed with a solution 2N aqueous hydrochloric acid and a saturated aqueous solution of sodium chloride, dried with magnesium sulfate, filtered and It is concentrated under vacuum. By flash chromatography (gel 20 Merck silica 60, 230-400 mesh, 98: 2 methylene chloride / methanol) tert-butyl [1- (7-methoxy-thiazolo [5,4-b] pyridin-2-carbamoyl) -pyrrolidin-3-yl] -carbamate (160) mg, 15%) as a slightly yellow solid. EM-LR of C17H23N5O4S (M + H) + at m / z = 393. The NMR spectrum obtained from the 25 sample is compatible with the structure of the compound.

OR image5

OR image5

image5 OR

image5 OR

image5 N

image5 OR

image5 N

TFA

NN image5

NN image5

H

S NO image5

S H NH2

N

N

H

Step 2: Stir at 25 ° C for 30 min a mixture of [1- (7-Methoxy-thiazolo [5,4-b] pyridin-2-ylcarbamoyl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester (160 mg, 0.41 mmol), acid

5 trifluoroacetic (6 ml) and methylene chloride (6 ml). The reaction mixture is then concentrated in vacuo, obtaining a red oil. The oil is crushed with ether, 3-amino acid (7-methoxy-thiazolo [5,4-b] pyridine-2-yl) -amide trifluoroacetic acid salt being obtained

10 pyrrolidine-1-carboxylic acid (160 mg, 99%) as a solid slightly brown

image5 OR

OR image5

OR image5

image5 OR

image5 OR

H

image5 N

image5 N

image5 F

TFA

F

NN image5

NN image5

H NH2 + F

H

S

SN

N

N

F

H

F

F

F

F

Step 3: a suspension of the acid salt is treated 3-Amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-b] pyridine-2-yl) 15 amide trifluoroacetic acid (160 mg, 0.39 mmol) in methanol with N, N-diisopropylethylamine (0.28 ml, 1.57 mmol). The reaction mixture is stirred at 25 ° C for 30 min. Then the methanol is removed under vacuum. Be add 4-fluor-3- (trifluoromethyl) benzaldehyde to the flask 20 (0.08 ml, 0.59 mmol) and toluene and the mixture is stirred resulting at 60 ° C for 1 h and then concentrated in vacuo. This procedure is repeated until the reaction mixture be homogeneous when dissolved in toluene. after one

final concentration to remove toluene, the reaction mixture with dichloroethane (15 ml) and treated with acetic acid (94 mg) and sodium triacetoxyborohydride (250 mg, 1.18 mmol). The resulting reaction mixture is maintained. 5 under stirring at 25oC overnight. Then the reaction mixture on 1N NaOH and extracted with chloride methylene The organic phase is washed with an aqueous solution. saturated with sodium bicarbonate, dried with sodium sulfate, Filter and concentrate under vacuum. By flash chromatography 10 (Merck silica gel 60, 230-400 mesh, 98: 2 chloride methylene / methanol) a colorless oil is obtained. It dissolves the oil in diethyl ether and concentrated in vacuo, obtaining (7-methoxy-thiazolo [5,4-b] pyridin-2-yl) -amide 3- (4-fluor-3-trifluoromethyl-benzylamino) acid

15 pyrrolidine-1-carboxylic acid (19 mg, 25%) as a solid White. LRMS of C20H19F4N5O2S (M + H) + at m / z = 469. The spectrum NMR obtained from the sample is compatible with the structure of the compound.

Example 102 Acid 20 (7-methoxy-thiazolo [5,4-b] pyridin-2-yl) -amide 4- (3-Trifluoromethyl-benzyl) -piperazine-1-carboxylic

image5 image5 OR

HN image5 image5 N

Cl N N

F

F

F

F

F

F

image5

Step 1: under nitrogen atmosphere it is treated slowly a stirred mixture with magnetic triphosgene rod (365

mg, 1.23 mmol) and tetrahydrofuran (20 ml) with pyridine (485 mg, 6.15 mmol) added with a syringe. It is the resulting white solution with a solution of 1- (3trifluoromethyl-benzyl) piperazine (1.0 g, 4.10 mmol) in 5 tetrahydrofuran (10 ml) added from a separatory funnel for 10 min. The reaction mixture is stirred at 25 ° C during one night The reaction mixture is then filtered to separate the solids. The liquid is concentrated vacuum filtered. By flash chromatography (silica gel 60

10 from Merck, 230-400 mesh, 60:40 hexanes / ethyl acetate) are obtains 4- (3-trifluoromethyl-benzyl) -piperazine-1-carbonyl chloride (350 mg, 28%) as a clear oil. He NMR spectrum obtained from the sample is compatible with the compound structure

OR image5 image5 OR

image5 OR image5 OR

image5 NH2

N + Cl N N

NN image5 image5 N image5

HS

N Cl

N

F

F

F F

F

F image5

fifteen

Step 2: a nitrogen atmosphere is treated at 25 ° C stirred mixture with magnetic rod of 4- (3trifluoromethyl-benzyl) -piperazine-1-carbonyl chloride (500 mg, 1,630

20 mmol) and acetone (20 ml) with ammonium thiocyanate (115 mg, 1.49 mmol). The reaction mixture is stirred at reflux for 30 min. The reaction mixture is then treated with 3 amino-2- chloro-4-methoxypyridine (215 mg, 1.34 mmol). Be keeps the reaction mixture boiling at reflux

during one night The mixture is then concentrated Reactant with vacuum, poured over water and extracted with ethyl acetate. The organic phase is washed with a solution aqueous saturated with sodium chloride, dried with sulfate magnesium, filtered and concentrated in vacuo. By flash chromatography (Merck silica gel 60, 230-400 mesh,

75:25 hexanes / ethyl acetate) 4- (3-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxythiazolo [5,4-b] pyridin-2-yl) -amide (35) mg, 15%) as white solid LRMS of C20H20F3N5O2S (M + H) + at m / z = 451. The NMR spectrum obtained from the sample is compatible with the compound structure

Example 103

Inhibitory activity of cyclic AMP production induced by NECA in CHO.K1 cells expressing the receptor of human A2B adenosine.

Ovarian cells of Chinese hamster (CHO.K1) stably transfected with the human A2B adenosine receptor cDNA 4b. They are cultivated cells in an atmosphere of 5% CO2 / 95% O2 at 37 ° C in a DMEM and D-MEM / F-12 medium (1: 1 mixture) (Invitrogen, Grand Island, NY) with 10% fetal bovine serum (Invitrogen, Grand Island, NY), 100 U / ml penicillin (Invitrogen, Grand Island, NY), 100 U / ml streptomycin (Invitrogen, Grand Island, NY), 1 mg / ml of G418 (Invitrogen, Grand Island NY) and 0.2mg / ml hygromycin B (Invitrogen, Carlsbad, CA). The experimental cultures are kept overnight in Monolayer shape in 384 tissue culture plates

holes (0.06 ml / hole -7500 cells / hole). Each hole is washed once with 0.1 ml of Krebs buffer. Each hole is add 50 µl of Krebs buffer containing 100 µM of the phosphodiesterase inhibitor, 4- (3-butoxy-4-methoxybenzyl) 5 2-imidazolidinone, 100 nM NECA (Sigma-Aldrich, St. Louis, MO), 0.02% BSA fraction V (Roche Biochemicals) and the compound to be tested (in an appropriate concentration). Concentration Final DMSO is 1.1%. After an incubation of 3045 min the holes are emptied and gently tapped on a 10 blotting paper to remove residual solution. For him adherent cell lysate the kit called HitHunterTM cAMP Assay Kit from DiscoverX (Fremont, CA) and also for measuring the concentrations of CAMP The compounds of examples 1-102 have values

15 of IC50 between concentrations 1 nanomolar and 10 micromolar, preferably between 1 nanomolar and 1 micromolar. Specific representative examples are collected in the following table I. Table I

example compound

IC50 (µM)

one

0.005

10

0.030

16

0.197

27

1,560

31

0.009

48

0.009

54

1,462

57

0.052

example compound

IC50 (µM)

62

0.218

67

0.051

76

0.073

87

0.002

89

0.004

95

0.115

Example A

Tablets can be manufactured by conventional methods film coated containing the following ingre

teeth:

Ingredients

per tablet

nucleus:

compound of the formula (I)

10.0 mg 200.0 mg

microcrystalline cellulose

23.5 mg 43.5 mg

hydrated lactose

60.0 mg 70.0 mg

Povidone K30

12.5 mg 15.0 mg

sodium starch glycolate

12.5 mg 17.0 mg

magnesium stearate

1.5 mg 4.5 mg

(core weight)

120.0 mg 350.0 mg

film layer:

hydroxypropyl methyl cellulose

3.5 mg 7.0 mg

6000 polyethylene glycol

0.8 mg 1.6 mg

talcum powder

1.3 mg 2.6 mg

iron oxide (yellow)

0.8 mg 1.6 mg

titanium dioxide

0.8 mg 1.6 mg

The active ingredient is screened and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulated with sodium starch glycolate and magnesium stearate

5 and compressed, obtaining cores of 120 and 350 mg, respectively. The cores are varnished with an aqueous solution / suspension of the fresh film layer composition described.

Example B 10 Conventional methods can be manufactured capsules containing the following ingredients:

Ingredients per capsule compound of the formula (I) 25.0 mg lactose 150.0 mg corn starch 20.0 mg talc 5.0 mg

The components are screened, mixed and packed in capsules size 2. Example C 15 Injectable solutions may have the composition next:

compound of the formula (I) 3.0 mg polyethylene glycol 400 150.0 mg acetic acid, sufficient amount up to pH = 5.0 water for injectable solutions, up to 1.0 ml

The active ingredient is dissolved in a mixture of

polyethylene glycol 400 and water for injections (one part). Be

Adjust the pH to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the remaining amount of water. Be filter the solution, pack it in vials using an excess appropriate and sterilized.

5 Example D By conventional methods capsules can be manufactured of soft gelatin containing the following ingredients.

Capsule Content compound of the formula (I) 5.0 mg yellow wax 8.0 mg hydrogenated soybean oil 8.0 mg partially hydrogenated vegetable oils 34.0 mg soybean oil 110.0 mg capsule content weight 165.0 mg gelatin capsule gelatin 75.0 mg glycerin 85% 32.0 mg Karion 83 8.0 mg

(dry material) 0.4 mg titanium dioxide 1.1 mg yellow iron oxide

The active ingredient is dissolved in a melt of the other ingredients and the mixture is packaged in capsules

10 soft gelatin of the appropriate size. The capsules of soft gelatin and its contents are treated according to usual procedures

Example E In a conventional way you can make sachets that contain the following ingredients:

compound of the formula (I) 50.0 mg lactose, fine powder 1015.0 mg microcrystalline cellulose (AVICEL PH 102) 1400.0 mg sodium carboxymethyl cellulose 14.0 mg polyvinylpyrrolidone K 30 10.0 mg magnesium stearate 10.0 mg flavoring additives 1.0 mg

The active ingredient is mixed with lactose, the ce

5 microcrystalline lulose and sodium carboxymethyl cellulose and se granulate with a mixture of polyvinylpyrrolidone and water. Be mix the granulate with magnesium stearate and additives Flavoring and packed in sachets. -.

10

Claims (16)

1. A compound of the formula I R1 5 in which X is C or N, R1 is C1-4 alkoxy, R2 is hydrogen, hydroxy, C1-2 alkoxy or C1-2 alkylthio, R3 is hydrogen or C1-3 alkyl, R4 is C1-4alkyl substituted by aryl, aroyl, aryloxy, arylsulfonyl, aralkylamino, or aroylamino, or R3 and R4 together with the urea nitrogen to which they are attached form a heterocyclic ring of 5 or 6 links of the form 15 mule in which R3 and R4 are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, It is already a saturated or partially unsaturated alkyl segment 20 from 2 to 3 carbons of the ring having an aromatic substituent selected from the group consisting of aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, image 1 image2 aryloxyalkyl, aryloxyalkylamino and aroylamino, e You can now also have 0, 1 or 2 non-aromatic substituents chosen between hydroxy, amino, lower alkylamino, alkanoylamino lower, oxo, cyano, carboxy, hydroxyalkylamino, carbamoyl 5 and (lower alkyl) carbamoyl, or R3 and R4 together with the urea nitrogen to which they are attached they form a heterocyclic ring of 5 or 6 links of the formula image3 R3 N R4 10 in which R3 and R4 are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, Yh is a saturated heteroalkyl segment of 2 or 3 atoms of the ring, one of which is a heteroatom and Yh is substituted by an aromatic group, which in the case of an atom of Ring carbon is chosen from the group formed by aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino or, in the case of nitrogen, is chosen from the group formed by aryl, 20 aralkyl, aroyl, arylhydroxymethyl alkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, arylsulfonyl, aryloxyalkyl, arylaminoalkyl and aroylaminoalkyl, or R3 and R4 together with the urea nitrogen to which they are attached 25 form a piperidinyl or pyrrolidinyl, which is benzo fused with an unsubstituted or mono-, di- or trisubstituted phenyl, or R3 and R4 together with the urea nitrogen to which they are attached they form a piperidinyl, which is spiro-fused with a 5 or 6-link saturated heterocyclic ring containing 1 or 2 heteroatoms, said heterocyclic ring is attached or benzo-fused with an unsubstituted or mono-, di-o phenyl tri-substituted and said heterocyclic ring may have also 0, 1 or 2 non-aromatic substituents chosen from lower alkyl, acyl and lower alkylsulfonyl, or R3 and R4 together with the urea nitrogen to which they are attached they form a 2,5-diaza- [2.2.1] -bicycloheptane substituted in position 5 or a 2,5-diaza- [3.3.0] -bicyclooctane substituted in position 5, said substituent of position 5 is chosen between the group consisting of aryl, aralkyl, aroyl, arylsulfonyl, aryloxyalkyl and arylhydroxymethyl alkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, or pharmaceutically acceptable salts or esters thereof, where the term "lower alkyl", alone or in combination, means an alkyl group containing a maximum of six carbon atoms. 2. The compound of claim 1, wherein R3 and R4 together with the urea nitrogen to which they are attached they form a heterocyclic ring of 5 or 6 links of the formula in which R3 and R4 are both CH2 or one is CH2 and the other is a methylene monosubstituted by a lower alkyl, It is already a saturated or partially unsaturated alkyl segment 5 of 2 to 3 carbons of the ring having a substituent aromatic chosen from the group formed by aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino, e You can also have 0, 1 or 2 substituents 10 aromatics chosen from hydroxy, amino, alkylamino lower, lower alkanoylamino, oxo, cyano, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) carbamoyl, or 15 R3 and R4 together with the urea nitrogen to which they are attached they form a heterocyclic ring of 5 or 6 links of the formula in which R3 and R4 are both CH2 or one is CH2 and the other is a 20 methylene monosubstituted by a lower alkyl, Yh is a saturated heteroalkyl segment of 2 or 3 atoms of the ring one of which is a heteroatom and Yh is substituted by an aromatic group, which in the case of an atom Carbon ring is chosen from the group consisting of image2 image4 aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino or, in the case of nitrogen, is chosen from the group formed by aryl, aralkyl, aroyl, arylhydroxymethylalkyl, arylcarboxymethyl alkyl, arylalkoxymethyl alkyl, arylsulfonyl, aryloxyalkyl, arylaminoalkyl and aroylaminoalkyl. 3. The compound of claim 1, wherein R3 and R4 together with the urea nitrogen to which they are attached they form a piperidinyl or pyrrolidinyl ring, which is benzo-fused with an unsubstituted or mono-, di-o phenyl tri-substituted

Four.

The compound of claim 1, wherein R3 and R4 together with the urea nitrogen to which they are attached they form a piperidinyl or pyrrolidinyl, which is spiro- fused with a saturated heterocyclic ring of 5 or 6 links containing 1 or 2 heteroatoms, said ring heterocyclic is attached or benzo-fused with a phenyl without substitute or mono-, di-or tri-substituted, and said ring heterocyclic may also have 0, 1 or 2 substituents not aromatics chosen from lower alkyl, acyl and lower alkylsulfonyl.

5.

The compound of claim 3 wherein the heterocyclic ring formed with R3 and R4 is pyrrolidinyl, piperidinyl or piperazinyl.

6.

The compounds of claim 9, which have the formula:

image5 R1 in which R5 is aryl, aralkyl, aroyl, aryloxyalkyl, arylsulfonyl, arylaminoalkyl, arylhydroxymethyl alkyl, arylalkoxy Methylalkyl, arylcarboxymethyl alkyl or aroylaminoalkyl. 7. The compound of claim 5, which has the formula image6 R1 N image6 XH image6 R6 N image6 SN image6 image6 R7 R2 N R8 OR , wherein one of R6-R8 is CH2, one of R6-R8 is CH2 or CH (OH) and 10 one of R6-R8 is a methylene having a substituent aromatic or two substituents: one aromatic and one not aromatic, said aromatic substituent is chosen from aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and Aroylamino and said non-aromatic substituent is chosen from hydroxy, cyano, amino, lower alkylamino, alkanoylamino lower, carboxy, hydroxyalkylamino, carbamoyl and (alkyl lower) carbamoyl. 8. The compound of claim 5, which has the 20 formula image6 R1 N image6 XH image6 R9 N image6 SN image6 R2 N R10 OR in which one of R9 and R10 is CH2 and the other is a methylene that It has an aromatic substituent or two substituents: one aromatic and other non-aromatic, said aromatic substituent 5 is chosen from aryl, aralkyl, aralkyloxy, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino and aroylamino and said substituent not aromatic is chosen from hydroxy, cyano, amino, alkylamino, carboxy, hydroxyalkylamino, carbamoyl and (lower alkyl) 10 carbamoyl. 9. The compound of claim 5, which has the formula image7 in which R11 is aryl, aroyl, aryloxy or arylsulfonyl and n is 1-4. 10. The compound of claim 1 of the formula image6 image6 R1 R12 N image6 X H N N SN R2 N OR OR image8 image9 in which Z is carbon or nitrogen and R12 is unsubstituted or mono-, di- or tri-substituted phenyl. 11. The compound according to claim 1, which has 5 the formula R1 wherein R13 is hydrogen, lower alkyl or lower alkylsulfonyl and R14 is hydrogen, halogen, lower alkyl or lower alkylsulfonyl. The compound of claim 1, which has the formula image6 R1 image6 R15 N image6 Hx image6 NN image6 N R2 SN O in which R15 is chosen from the group consisting of aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, 15 aryloxyalkyl, aryloxyalkylamino, aroylamino, arylhydroxymethyl alkyl, arylcarboxymethyl alkyl and arylalkoxymethyl alkyl. 13. The compound according to claim 1 of the formula image10 in which R16 is chosen from the group consisting of aryl, aralkyl, aroyl, aryloxy, arylsulfonyl, aralkylamino, aryloxyalkyl, aryloxyalkylamino, aroylamino, arylhydroxy 5-methylalkyl, arylcarboxymethyl-alkyl and arylalkoxymethyl-alkyl. 14. The compound according to claim 1, which is Choose from the group consisting of: 4- (3-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 10 trifluoromethyl-benzyl) -piperazine-1-carboxylic acid, 4- (3-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2-Chloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 20-methoxy-benzyl) -piperazine-1-carboxylic acid, 4 (3,4-Difluoro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-4-methoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4- (3-nitrobenzyl) -piperazine-1-carboxylic acid, Methyl 3- [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-ylmethyl] -benzoate, 4 (3,5-Dimethoxy-benzyl) piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Trifluoromethoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3difluoromethoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (3,5-Dichloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- [3 (2-Hydroxy-ethoxy) -benzyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- [1 (3-Chloro-phenyl) -ethyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Phenethyl-piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-3-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (6-Trifluoromethyl-pyridin-3-ylmethyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (5-Chloro-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, {3- [4- (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) acid piperazin-1-ylmethyl] -phenoxy} -acetic acid, 4 (3,5-Dichloro-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (5-methoxythiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3fluor-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (5fluor-2-hydroxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2-Hydroxy-3-methyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 2-hydroxy-3- [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-ylmethyl] -benzoic acid, 4- (6morpholin-4-yl-pyridin-3-yl-methyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Benzyl-piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Chloro-2-methanesulfonyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (3,4-Dichloro-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Methoxy-3-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3ciano-4-methoxy-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (3,5-bis-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- [2 (3-Trifluoromethyl-phenoxy) -ethyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-3-trifluoromethyl-benzoyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (6-Trifluoromethyl-pyridine-3-carbonyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-benzoyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-benzenesulfonyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- [3 (Trifluoromethyl) phenyl] piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 2- (4-Trifluoromethyl-phenyl) -morpholine-4-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 1 - [(7-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide] 3-thiazol-2-amide of piperidine-1,3-dicarboxylic acid, 4- (5methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide , 1- (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -3- (4-trifluoromethoxy-benzyl) -piperidine-3-carboxylate ethyl, 4'hydroxy-3 ', 4', 5 ', 6'-tetrahydro-2H- [2,4'] bipyridinyl (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide -1'-carboxylic, 3,4-Hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (1,3-dihydro-isoindol-2-yl) -piperidine-1-carboxylic acid, trifluoroacetate, (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide; 4- (4fluor-phenyl) -1-oxo-2,8-diazapiro [4,5] decane-8-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide , 5-Chloro-1,2-dihydro-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) 1- (methylsulfonyl) spiro [3H-indole-3,4'-piperidine] -1 ' -carboxamide, 1,2-dihydro-5-methoxy-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) 1-methylpyrro [3H-indole-3,4'-piperidine] -1'-carboxamide, 1- (cyclopropylmethyl) -1,2-dihydro-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) spiro [3H-indole-3,4'-piperidine] -1'-carboxamide, 1- (cyclopropylmethyl) -1,2-dihydro-5-chloro-N- (7-methoxythiazol [5,4-d] pyrimidin-2-yl) spiro [3H-indole-3,4'-piperidine] -1 'carboxamide, 4- (4fluor-phenyl) -1-oxo-2,8-diaza-spiro [4.5] decane-8-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide; 4- (3-phenyl-pyrrolidin-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2-Phenyl-pyrrolidin-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (2,3-dihydro-indol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (5-Chloro-2,3-dihydro-indole-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3trifluoromethyl-phenyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3- (3-Trifluoromethyl-benzyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3-Benzyl-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (2oxo-2,3-dihydro-benzoimidazol-1-yl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Trifluoromethyl-benzenesulfonyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Chloro-benzenesulfonyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 (Toluene-4-sulfonyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-phenoxy) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-benzyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, Methyl 2- [1- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperidine-4-sulfonyl] -benzoate, 4- (3-Trifluoromethyl-benzyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (3-Chloro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Hydroxy-4- (3-methoxy-phenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4'hydroxy-6-trifluoromethyl-3 ', 4', 5 ', 6'-tetrahydro-2'H- [(7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide [[ 2,4 '] bipyridinyl-1'-carboxylic acid, 4-Acetylamino-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-amino-4- (3-trifluoromethyl-phenyl) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-3-trifluoromethyl-benzylamino) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4 [(6-Trifluoromethyl-pyridin-3-ylmethyl) -amino] -piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4- (4-Fluoro-3-trifluoromethyl-benzoylamino) -piperidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3- (4-Chloro-benzyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3- (4-Trifluoromethyl-benzyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3 (Toluene-4-sulfonyl) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 3- [2 (3-Trifluoromethyl-phenoxy) -ethylamino] -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, (R) 3- (4-Fluoro-3-trifluoromethyl-benzylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, (R) 3- (4-Fluoro-3-trifluoromethyl-benzoylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, (S) 3- (4-Fluoro-3-trifluoromethyl-benzoylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 8-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 6-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (5-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide. 4-fluor-N- {2- [3- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -ureido] -ethyl} -3-trifluoromethyl-benzamide, 1- [2- (4-fluor-3-trifluoromethyl-benzylamino) -ethyl] -3- (7-methoxythiazolo [5,4-d] pyrimidin-2-yl) -urea, 3- (7-Methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -1-methyl-1- [(7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 2- (3-Trifluoromethyl-phenoxy) -ethyl] urea-4- [1- (3-chloro-phenyl) -2-hydroxyethyl] -piperazine-1-carboxylic acid, (3-Chloro-phenyl) - [4- (7-methoxy-thiazolo [5,4-d] pyrimidin-2-ylcarbamoyl) -piperazin-1-yl] -methyl acetate, 4- [2-Methoxy-1- (3-trifluoromethyl-phenyl) -ethyl] -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide, 4-Hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) amide, (5-Hydroxy-7-methoxy-thiazolo [5,4-d] pyrimidin-2-yl) -amide 4-hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid, 4-Hydroxy-4- [3- (trifluoromethyl) phenyl] piperidine-1-carboxylic acid (5-methoxy-thiazolo [5,4-b] pyridine-2-yl) -amide, 3- (4-Fluoro-3-trifluoromethyl-benzylamino) -pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo [5,4-b] pyridin-2-yl) -amide Y 4- (3-Trifluoromethyl-benzyl) -piperazine-1-carboxylic acid (7-methoxy-thiazolo [5,4-b] pyridin-2-yl) -amide.

fifteen.

Pharmaceutical compositions containing a A2B receptor antagonist according to any one of the claims 1-14 and a pharmaceutically acceptable carrier and / or adjuvant.

16.

A2B receptor antagonists according to any one of claims 1-14 for use as therapeutically active substances.

17.

The use of A2B receptor antagonists according to a any one of claims 1-14 for manufacturing of medicines intended for therapeutic treatment and / or type 2 diabetes prophylactic, diabetic retinopathy, asthma, bronchospastic and allergic diseases, disorders inflammatory of the gastrointestinal tract and diarrhea.